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Nanoparticle Effects on Human Platelets in Vitro: A Comparison between PAMAM and Triazine Dendrimers.

Recent Research Articles from UNTHSC - Tue, 04/05/2016 - 10:29
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Nanoparticle Effects on Human Platelets in Vitro: A Comparison between PAMAM and Triazine Dendrimers.

Molecules. 2016;21(4)

Authors: Enciso AE, Neun B, Rodriguez J, Ranjan AP, Dobrovolskaia MA, Simanek EE

Abstract
Triazine and PAMAM dendrimers of similar size and number of cationic surface groups were compared for their ability to promote platelet aggregation. Triazine dendrimers (G3, G5 and G7) varied in molecular weight from 8 kDa-130 kDa and in surface groups 16-256. PAMAM dendrimers selected for comparison included G3 (7 kDa, 32 surface groups) and G6 (58 kDa, 256 surface groups). The treatment of human platelet-rich plasma (PRP) with low generation triazine dendrimers (0.01-1 µM) did not show any significant effect in human platelet aggregation in vitro; however, the treatment of PRP with larger generations promotes an effective aggregation. These results are in agreement with studies performed with PAMAM dendrimers, where large generations promote aggregation. Triazine dendrimers promote aggregation less aggressively than PAMAM dendrimers, a factor attributed to differences in cationic charge or the formation of supramolecular assemblies of dendrimers.

PMID: 27043508 [PubMed - as supplied by publisher]

Carbon Disulfide (CS2) Interference in Glucose Metabolism from Unconventional Oil and Gas Extraction and Processing Emissions.

Recent Research Articles from UNTHSC - Tue, 04/05/2016 - 10:29
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Carbon Disulfide (CS2) Interference in Glucose Metabolism from Unconventional Oil and Gas Extraction and Processing Emissions.

Environ Health Insights. 2016;10:51-7

Authors: Rich AL, Patel JT, Al-Angari SS

Abstract
Carbon disulfide (CS2) has been historically associated with the manufacturing of rayon, cellophane, and carbon tetrachloride production. This study is one of the first to identify elevated atmospheric levels of CS2 above national background levels and its mechanisms to dysregulate normal glucose metabolism. Interference in glucose metabolism can indirectly cause other complications (diabetes, neurodegenerative disease, and retinopathy), which may be preventable if proper precautions are taken. Rich et al found CS2 and 12 associated sulfide compounds present in the atmosphere in residential areas where unconventional shale oil and gas extraction and processing operations were occurring. Ambient atmospheric concentrations of CS2 ranged from 0.7 parts per billion by volume (ppbv) to 103 ppbv over a continuous 24-hour monitoring period. One-hour ambient atmospheric concentrations ranged from 3.4 ppbv to 504.6 ppbv. Using the U.S. Environmental Protection Agency Urban Air Toxic Monitoring Program study as a baseline comparison for atmospheric CS2 concentrations found in this study, it was determined that CS2 atmospheric levels were consistently elevated in areas where unconventional oil and gas extraction and processing occurred. The mechanisms by which CS2 interferes in normal glucose metabolism by dysregulation of the tryptophan metabolism pathway are presented in this study. The literature review found an increased potential for alteration of normal glucose metabolism in viscose rayon occupational workers exposed to CS2. Occupational workers in the energy extraction industry exposed to CS2 and other sulfide compounds may have an increased potential for glucose metabolism interference, which has been an indicator for diabetogenic effect and other related health impacts. The recommendation of this study is for implementation of regular monitoring of blood glucose levels in CS2-exposed populations as a preventative health measure.

PMID: 27042092 [PubMed]

Protein Modifications as Manifestations of Hyperglycemic Glucotoxicity in Diabetes and Its Complications.

Recent Research Articles from UNTHSC - Tue, 04/05/2016 - 10:29
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Protein Modifications as Manifestations of Hyperglycemic Glucotoxicity in Diabetes and Its Complications.

Biochem Insights. 2016;9:1-9

Authors: Zheng H, Wu J, Jin Z, Yan LJ

Abstract
Diabetes and its complications are hyperglycemic toxicity diseases. Many metabolic pathways in this array of diseases become aberrant, which is accompanied with a variety of posttranslational protein modifications that in turn reflect diabetic glucotoxicity. In this review, we summarize some of the most widely studied protein modifications in diabetes and its complications. These modifications include glycation, carbonylation, nitration, cysteine S-nitrosylation, acetylation, sumoylation, ADP-ribosylation, O-GlcNAcylation, and succination. All these posttranslational modifications can be significantly attributed to oxidative stress and/or carbon stress induced by diabetic redox imbalance that is driven by activation of pathways, such as the polyol pathway and the ADP-ribosylation pathway. Exploring the nature of these modifications should facilitate our understanding of the pathological mechanisms of diabetes and its associated complications.

PMID: 27042090 [PubMed]

Exosomes are unlikely involved in intercellular Nef transfer.

Recent Research Articles from UNTHSC - Tue, 04/05/2016 - 10:29
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Exosomes are unlikely involved in intercellular Nef transfer.

PLoS One. 2015;10(4):e0124436

Authors: Luo X, Fan Y, Park IW, He JJ

Abstract
HIV-1 Nef is an important pathogenic factor for HIV/AIDS pathogenesis. Several recent studies including ours have demonstrated that Nef can be transferred to neighboring cells and alters the function of these cells. However, how the intercellular Nef transfer occurs is in dispute. In the current study, we attempted to address this important issue using several complementary strategies, a panel of exosomal markers, and human CD4+ T lymphocyte cell line Jurkat and a commonly used cell line 293T. First, we showed that Nef was transferred from Nef-expressing or HIV-infected Jurkat to naïve Jurkat and other non-Jurkat cells and that the transfer required the membrane targeting function of Nef and was cell density-dependent. Then, we showed that Nef transfer was cell-cell contact-dependent, as exposure to culture supernatants or exosomes from HIV-infected Jurkat or Nef-expressing Jurkat and 293T led to little Nef detection in the target cells Jurkat. Thirdly, we demonstrated that Nef was only detected to be associated with HIV virions but not with acetylcholinesterase (AChE+) exosomes from HIV-infected Jurkat and not in the exosomes from Nef-expressing Jurkat. In comparison, when it was over-expressed in 293T, Nef was detected in detergent-insoluble AChE+/CD81 low/TSG101 low exosomes, but not in detergent-soluble AChE-/CD81 high/TSG101 high exosomes. Lastly, microscopic imaging showed no significant Nef detection in exosomal vesicle-like structures in and out 293T. Taken together, these results show that exosomes are unlikely involved in intercellular Nef transfer. In addition, this study reveals existence of two types of exosomes: AChE+/CD81 low/TSG101 low exosomes and AChE-/CD81 high/TSG101 high exosomes.

PMID: 25919665 [PubMed - indexed for MEDLINE]

A depressive endophenotype of poorer cognition among cognitively healthy community-dwelling adults: results from the Western Australia memory study.

Recent Research Articles from UNTHSC - Tue, 04/05/2016 - 10:29
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A depressive endophenotype of poorer cognition among cognitively healthy community-dwelling adults: results from the Western Australia memory study.

Int J Geriatr Psychiatry. 2015 Aug;30(8):881-6

Authors: Johnson LA, Sohrabi HR, Hall JR, Kevin T, Edwards M, O'Bryant SE, Martins RN

Abstract
OBJECTIVE: The objective was to evaluate in a cognitively normal population the utility of an endophenotype of the depression-cognition link previously shown to be related to cognitive functioning in mild cognitive impairment and Alzheimer's disease.
METHODS: The data of 460 cognitively normal adults aged 32-92 years (M = 63.5, standard deviation = 9.24) from the Western Australian Memory Study with the Cross-national comparisons of the Cambridge Cognitive Examination-revised (CAMCOG-R) scores and 30-item Geriatric Depression Scale (GDS) scores were analyzed to determine the relationship between the five-item depressive endophenotype (DepE) scale drawn from the GDS and level of performance on a measure of cognitive functioning.
RESULTS: For the entire sample, there was a nonsignificant trend toward a negative relationship between DepE and CAMCOG-R scores. When analyzed for those 65 years and older, there was a significant negative relationship between the two measures (p = 0.001) with DepE scores significantly increasing the risk for performing more poorly on the CAMCOG-R (odds ratio = 1.53). Analysis of data for those 70 years and older showed that DepE was the only predictor significantly related to poorer CAMCOG-R performance (p = 0.001). For the 70 years and older group, DepE scores significantly increased the risk of poorer CAMCOG-R scores (odds ratio = 2.23). Analysis of the entire sample on the basis of ApoEε4 carrier status revealed that DepE scores were significantly negatively related only to ApoEε4 noncarrier regardless of age.
CONCLUSIONS: Elevated DepE scores are associated with poor neuropsychological performance among cognitively normal older adults. Use of the DepE may allow for the identification of a subset of older adults where depression is a primary factor in cognitive decline and who may benefit from antidepressant therapies.

PMID: 25394326 [PubMed - indexed for MEDLINE]

U.S. Physicians' Opinions About Accommodating Religiously Based Requests for Continued Life-Sustaining Treatment.

Recent Research Articles from UNTHSC - Mon, 04/04/2016 - 06:31

U.S. Physicians' Opinions About Accommodating Religiously Based Requests for Continued Life-Sustaining Treatment.

J Pain Symptom Manage. 2016 Mar 30;

Authors: Ayeh DD, Tak HJ, Yoon JD, Curlin FA

Abstract
CONTEXT: Families of critically ill patients occasionally request that physicians continue life-sustaining treatment (LST), sometimes giving religious reasons.
OBJECTIVES: To examine whether U.S. physicians are more likely to accommodate requests for LST that are based on religious reasons.
METHODS: In 2010 we surveyed 1156 practicing U.S. physicians from specialties likely to care for adult patients with advanced illness. The questionnaire included two randomized experimental vignettes: one where a family asked that LST be continued for a patient that met brain death criteria and a second where the son of an elderly patient with cancer insists on continuing LST. In both, we experimentally varied the reasons that the family member gave to justify the request, to see if physicians are more likely to accommodate a request based on a religious requirement or hope for a miracle, compared to no mention of either. For physicians' religious characteristics, we assessed their religious affiliation and level of religiosity.
RESULTS: For the patient meeting brain death criteria, physicians were more likely to accommodate the request to continue LST when the family mentioned their Orthodox Jewish community (85% vs. 70%, P<0.001). For the patient with metastatic cancer, physicians were more likely to accommodate the request when the son said his religious faith does not permit discontinuing LST (65% vs. 46%, P<0.001), but not when he said he expected divine healing (50% vs. 46%).
CONCLUSION: Physicians appear more willing to accommodate requests to continue LST when those requests are based on particular religious communities or traditions, but not when based on expectations of divine healing.

PMID: 27039013 [PubMed - as supplied by publisher]

Conjunctival Lesions and Vision Impairment After Gastrointestinal Surgery.

Recent Research Articles from UNTHSC - Fri, 04/01/2016 - 06:43

Conjunctival Lesions and Vision Impairment After Gastrointestinal Surgery.

JAMA Ophthalmol. 2016 Mar 31;

Authors: Kirkland KA, Swann RE

PMID: 27031091 [PubMed - as supplied by publisher]

Locomotor, discriminative stimulus, and place conditioning effects of MDAI in rodents.

Recent Research Articles from UNTHSC - Thu, 03/31/2016 - 06:31

Locomotor, discriminative stimulus, and place conditioning effects of MDAI in rodents.

Behav Pharmacol. 2016 Mar 29;

Authors: Gatch MB, Dolan SB, Forster MJ

Abstract
5,6-Methylenedioxy-2-aminoindane (MDAI) has become a common substitute for (±)-3,4-methylenedioxymethamphetamine (MDMA) in Ecstasy. MDAI is known to produce MDMA-like discriminative stimulus effects, but it is not known whether MDAI has psychostimulant or hallucinogen-like effects. MDAI was tested for locomotor stimulant effects in mice and subsequently for discriminative stimulus effects in rats trained to discriminate cocaine (10 mg/kg, intraperitoneally), methamphetamine (1 mg/kg, intraperitoneally), ±MDMA (1.5 mg/kg, intraperitoneally), or (-)-2,5-dimethoxy-4-methylamphetamine hydrochloride (0.5 mg/kg, intraperitoneally) from saline. The ability of MDAI to produce conditioned place preference was also tested in mice. MDAI (3 to 30 mg/kg) depressed locomotor activity from 10 to 60 min. A rebound stimulant effect was observed at 1 to 3.5 h following 30 mg/kg. Lethality occurred in 8/8 mice following 100 mg/kg MDAI. Similarly, MDMA depressed locomotor activity immediately following the administration of 0.25 mg/kg and stimulant effects were observed 50-70 min following the administration of 0.5 and 1 mg/kg. MDAI fully substituted for the discriminative stimulus effects of MDMA (2.5 mg/kg), (-)-2,5-dimethoxy-4-methylamphetamine hydrochloride (5 mg/kg), and cocaine (7.5 mg/kg), but produced only 73% methamphetamine-appropriate responding at a dose that suppressed responding (7.5 mg/kg). MDAI produced tremors at 10 mg/kg in one methamphetamine-trained rat. MDAI produced conditioned place preference from 0.3 to 10 mg/kg. The effects of MDAI on locomotor activity and drug discrimination were similar to those produced by MDMA, having both psychostimulant-like and hallucinogen-like effects; thus, MDAI may have similar abuse potential as MDMA.

PMID: 27028902 [PubMed - as supplied by publisher]

N-Acetylcysteine reduces hyperacute intermittent hypoxia-induced sympathoexcitation in human subjects.

Recent Research Articles from UNTHSC - Thu, 03/31/2016 - 06:31

N-Acetylcysteine reduces hyperacute intermittent hypoxia-induced sympathoexcitation in human subjects.

Exp Physiol. 2016 Mar 1;101(3):387-396

Authors: Jouett NP, Moralez G, White DW, Eubank WL, Chen S, Tian J, Smith ML, Zimmerman MC, Raven PB

Abstract
NEW FINDINGS: What is the central question of this study? This study evaluated the following central question: does N-acetylcysteine (N-AC), an antioxidant that readily penetrates the blood-brain barrier, have the capability to reduce the increase in sympathetic nerve activity observed during hyperacute intermittent hypoxia? What is the main finding and its importance? We demonstrate that N-AC decreases muscle sympathetic nerve activity in response to hyperacute intermittent hypoxia versus placebo control. This finding suggests that antioxidants, such as N-AC, have therapeutic potential in obstructive sleep apnoea. This investigation tested the following hypotheses: that (i) N-acetylcysteine (N-AC) attenuates hyperacute intermittent hypoxia-induced sympathoexcitation, (ii) without elevating superoxide measured in peripheral venous blood. Twenty-eight healthy human subjects were recruited to the study. One hour before experimentation, each subject randomly ingested either 70 mg kg(-1) of N-AC (n = 16) or vehicle placebo (n = 12). Three-lead ECG and arterial blood pressure, muscle sympathetic nerve activity (n = 17) and whole-blood superoxide concentration (using electron paramagnetic resonance spectroscopy; n = 12) were measured. Subjects underwent a 20 min hyperacute intermittent hypoxia training (hAIHT) protocol that consisted of cyclical end-expiratory apnoeas with 100% nitrogen. N-AC decreased muscle sympathetic nerve activity after hAIHT compared with placebo (P < 0.02). However, N-AC did not alter superoxide concentrations in venous blood compared with placebo (P > 0.05). Moreover, hAIHT did not increase superoxide concentrations in the peripheral circulation as measured by electron paramagnetic resonance (P > 0.05). Based on these findings, we contend that (i) hAIHT and (ii) the actions of N-AC in hAIHT are primarily mediated centrally rather than peripherally, although central measurements of reactive oxygen species are difficult to obtain in human subjects, thus making this assertion difficult to verify. This investigation suggests the possibility of developing a pharmaceutical therapy to inhibit the sympathoexcitation associated with obstructive sleep apnoea.

PMID: 27027616 [PubMed - as supplied by publisher]

Effects of the Ion PGM™ Hi-Q™ sequencing chemistry on sequence data quality.

Recent Research Articles from UNTHSC - Thu, 03/31/2016 - 06:31

Effects of the Ion PGM™ Hi-Q™ sequencing chemistry on sequence data quality.

Int J Legal Med. 2016 Mar 30;

Authors: Churchill JD, King JL, Chakraborty R, Budowle B

Abstract
Massively parallel sequencing (MPS) offers substantial improvements over current forensic DNA typing methodologies such as increased resolution, scalability, and throughput. The Ion PGM™ is a promising MPS platform for analysis of forensic biological evidence. The system employs a sequencing-by-synthesis chemistry on a semiconductor chip that measures a pH change due to the release of hydrogen ions as nucleotides are incorporated into the growing DNA strands. However, implementation of MPS into forensic laboratories requires a robust chemistry. Ion Torrent's Hi-Q™ Sequencing Chemistry was evaluated to determine if it could improve on the quality of the generated sequence data in association with selected genetic marker targets. The whole mitochondrial genome and the HID-Ion STR 10-plex panel were sequenced on the Ion PGM™ system with the Ion PGM™ Sequencing 400 Kit and the Ion PGM™ Hi-Q™ Sequencing Kit. Concordance, coverage, strand balance, noise, and deletion ratios were assessed in evaluating the performance of the Ion PGM™ Hi-Q™ Sequencing Kit. The results indicate that reliable, accurate data are generated and that sequencing through homopolymeric regions can be improved with the use of Ion Torrent's Hi-Q™ Sequencing Chemistry. Overall, the quality of the generated sequencing data supports the potential for use of the Ion PGM™ in forensic genetic laboratories.

PMID: 27025714 [PubMed - as supplied by publisher]

Δ9-Tetrahydrocannabinol-like effects of novel synthetic cannabinoids found on the gray market.

Recent Research Articles from UNTHSC - Wed, 03/30/2016 - 06:40
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Δ9-Tetrahydrocannabinol-like effects of novel synthetic cannabinoids found on the gray market.

Behav Pharmacol. 2015 Aug;26(5):460-8

Authors: Gatch MB, Forster MJ

Abstract
When synthetic cannabinoid compounds became controlled by state and federal governments, different, noncontrolled compounds began to appear as marijuana substitutes. Unlike the scheduled cannabinoids, the newer compounds have not been characterized for potency and efficacy in preclinical studies. The purpose of these experiments was to determine whether some of the more recent synthetic compounds sold as marijuana substitutes have behavioral effects similar to those of Δ-tetrahydrocannabinol (Δ-THC), the pharmacologically active compound in marijuana. The compounds UR-144, XLR-11, AKB-48 (APINACA), PB-22 (QUPIC), 5F-PB-22, and AB-FUBINACA were tested for locomotor depressant effects in male Swiss-Webster mice and subsequently for their ability to substitute for Δ-THC (3 mg/kg, intraperitoneally) in drug discrimination experiments with male Sprague-Dawley rats. UR-144, XLR-11, AKB-48, and AB-FUBINACA each decreased locomotor activity for up to 90 min, whereas PB-22 and 5F-PB-22 produced depressant effects lasting 120-150 min. Each of the compounds fully substituted for the discriminative stimulus effects of Δ-THC. These findings confirm the suggestion that these compounds have marijuana-like psychoactive effects and abuse liability.

PMID: 26061356 [PubMed - indexed for MEDLINE]

ERG oncoprotein inhibits ANXA2 expression and function in prostate cancer.

Recent Research Articles from UNTHSC - Wed, 03/30/2016 - 06:40
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ERG oncoprotein inhibits ANXA2 expression and function in prostate cancer.

Mol Cancer Res. 2015 Feb;13(2):368-79

Authors: Griner NB, Young D, Chaudhary P, Mohamed AA, Huang W, Chen Y, Sreenath T, Dobi A, Petrovics G, Vishwanatha JK, Sesterhenn IA, Srivastava S, Tan SH

Abstract
UNLABELLED: Overexpression of ERG in the prostate epithelium, due to chromosomal translocations, contributes to prostate tumorigenesis. Here, genomic analysis of ERG siRNA-treated prostate cells harboring the endogenous TMPRSS2-ERG fusion revealed an inverse relationship between ERG and Annexin A2 (ANXA2) expression at both the RNA and protein level. ANXA2, a Ca(2+)-dependent and phospholipid-binding protein, is involved in various cellular functions, including maintenance of epithelial cell polarity. Mechanistic studies defined the prostate-specific transcription start site of ANXA2 and showed that the recruitment of ERG to the ANXA2 promoter is required for transcriptional repression by ERG. Knockdown of ERG enhanced the apical localization of ANXA2, the bundling of actin filaments at cell-cell junctions and formation of a polarized epithelial phenotype. ERG overexpression disrupted ANXA2-mediated cell polarity and promoted epithelial-mesenchymal transition (EMT) by inhibiting CDC42 and RHOA, and by activating cofilin. Immunohistochemistry demonstrated a reciprocal relationship of ANXA2 and ERG expression in a large fraction of primary prostate cancer clinical specimens. ANXA2 was absent or markedly reduced in ERG(+) tumors, which were mostly well differentiated. ERG(-) tumors, meanwhile, expressed moderate to high levels of ANXA2, and were either poorly differentiated or displayed subsets of poorly differentiated cells. Taken together, the transcriptional repression of ANXA2 by ERG in prostate epithelial cells plays a critical role in abrogating differentiation, promoting EMT, and in the reciprocal correlation of ERG and ANXA2 expression observed in human prostate cancer.
IMPLICATIONS: ANXA2 is a new component of the ERG network with potential to enhance biologic stratification and therapeutic targeting of ERG-stratified prostate cancers.

PMID: 25344575 [PubMed - indexed for MEDLINE]

Comparing biological markers of Alzheimer's disease across blood fraction and platforms: Comparing apples to oranges.

Recent Research Articles from UNTHSC - Tue, 03/29/2016 - 06:29

Comparing biological markers of Alzheimer's disease across blood fraction and platforms: Comparing apples to oranges.

Alzheimers Dement (Amst). 2016;3:27-34

Authors: O'Bryant SE, Lista S, Rissman RA, Edwards M, Zhang F, Hall J, Zetterberg H, Lovestone S, Gupta V, Graff-Radford N, Martins R, Jeromin A, Waring S, Oh E, King M, Baker L, Hampel H

Abstract
INTRODUCTION: This study investigated the comparability of potential AD biomarkers across blood fractions and assay platforms.
METHODS: Non-fasting serum and plasma samples from 300 participants (150 AD patients, 150 controls) were analyzed. Proteomic markers were obtained via electrochemiluminescence or Luminex technology. Comparisons were conducted via Pearson correlations. The relative importance of proteins within an AD diagnostic profile was examined using random forest importance plots.
RESULTS: On the MSD multi-plex platform, 10 out of the 21 markers shared >50% of the variance across blood fractions (SAA R(2)=0.99, IL10 R(2)=0.95, FABP R(2)=0.94, I309 R(2)=0.94, IL5 R(2)=0.94, IL6 R(2)=0.94, Eotaxin3 R(2)=0.91, IL18 R(2)=0.87, sTNFR1 R(2)=0.85, PPY R(2)=0.81). When examining protein concentrations across platforms, only five markers shared >50% of the variance (β2M R(2)=0.92, IL18 R(2)=0.80, FVII R(2)=0.78, CRP R(2)=0.74, FABP R(2)=0.70).
DISCUSSION: The current findings highlight the importance of considering blood fractions and assay platforms when searching for AD relevant biomarkers.

PMID: 27019866 [PubMed - as supplied by publisher]

Antiangiogenic mechanisms and factors in breast cancer treatment.

Recent Research Articles from UNTHSC - Sat, 03/26/2016 - 06:37

Antiangiogenic mechanisms and factors in breast cancer treatment.

J Carcinog. 2016;15:1

Authors: Castañeda-Gill JM, Vishwanatha JK

Abstract
Breast cancer is known to metastasize in its latter stages of existence. The different angiogenic mechanisms and factors that allow for its progression are reviewed in this article. Understanding these mechanisms and factors will allow researchers to design drugs to inhibit angiogenic behaviors and control the rate of tumor growth.

PMID: 27013929 [PubMed]

Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria.

Recent Research Articles from UNTHSC - Sat, 03/26/2016 - 06:37

Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria.

Alzheimers Dement. 2016 Mar;12(3):292-323

Authors: Dubois B, Hampel H, Feldman HH, Scheltens P, Aisen P, Andrieu S, Bakardjian H, Benali H, Bertram L, Blennow K, Broich K, Cavedo E, Crutch S, Dartigues JF, Duyckaerts C, Epelbaum S, Frisoni GB, Gauthier S, Genthon R, Gouw AA, Habert MO, Holtzman DM, Kivipelto M, Lista S, Molinuevo JL, O'Bryant SE, Rabinovici GD, Rowe C, Salloway S, Schneider LS, Sperling R, Teichmann M, Carrillo MC, Cummings J, Jack CR, Proceedings of the Meeting of the International Working Group (IWG) and the American Alzheimer's Association on “The Preclinical State of AD”; July 23, 2015; Washington DC, USA

Abstract
During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this "silent" stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations.

PMID: 27012484 [PubMed - in process]

Large-scale recent expansion of European patrilineages shown by population resequencing.

Recent Research Articles from UNTHSC - Sat, 03/26/2016 - 06:37
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Large-scale recent expansion of European patrilineages shown by population resequencing.

Nat Commun. 2015;6:7152

Authors: Batini C, Hallast P, Zadik D, Delser PM, Benazzo A, Ghirotto S, Arroyo-Pardo E, Cavalleri GL, de Knijff P, Dupuy BM, Eriksen HA, King TE, López de Munain A, López-Parra AM, Loutradis A, Milasin J, Novelletto A, Pamjav H, Sajantila A, Tolun A, Winney B, Jobling MA

Abstract
The proportion of Europeans descending from Neolithic farmers ∼ 10 thousand years ago (KYA) or Palaeolithic hunter-gatherers has been much debated. The male-specific region of the Y chromosome (MSY) has been widely applied to this question, but unbiased estimates of diversity and time depth have been lacking. Here we show that European patrilineages underwent a recent continent-wide expansion. Resequencing of 3.7 Mb of MSY DNA in 334 males, comprising 17 European and Middle Eastern populations, defines a phylogeny containing 5,996 single-nucleotide polymorphisms. Dating indicates that three major lineages (I1, R1a and R1b), accounting for 64% of our sample, have very recent coalescent times, ranging between 3.5 and 7.3 KYA. A continuous swathe of 13/17 populations share similar histories featuring a demographic expansion starting ∼ 2.1-4.2 KYA. Our results are compatible with ancient MSY DNA data, and contrast with data on mitochondrial DNA, indicating a widespread male-specific phenomenon that focuses interest on the social structure of Bronze Age Europe.

PMID: 25988751 [PubMed - indexed for MEDLINE]

Wikipedia vs peer-reviewed medical literature for information about the 10 most costly medical conditions-III.

Recent Research Articles from UNTHSC - Sat, 03/26/2016 - 06:37
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Wikipedia vs peer-reviewed medical literature for information about the 10 most costly medical conditions-III.

J Am Osteopath Assoc. 2014 Oct;114(10):764-5

Authors: Chen GS, Xiong Y

PMID: 25288709 [PubMed - indexed for MEDLINE]

C1q propagates microglial activation and neurodegeneration in the visual axis following retinal ischemia/reperfusion injury.

Recent Research Articles from UNTHSC - Fri, 03/25/2016 - 06:29

C1q propagates microglial activation and neurodegeneration in the visual axis following retinal ischemia/reperfusion injury.

Mol Neurodegener. 2016;11(1):24

Authors: Silverman SM, Kim BJ, Howell GR, Miller J, John SW, Wordinger RJ, Clark AF

Abstract
BACKGROUND: C1q represents the initiating protein of the classical complement cascade, however recent findings indicate pathway independent roles such as developmental pruning of retinal ganglion cell (RGC) axons. Furthermore, chronic neuroinflammation, including increased expression of C1q and activation of microglia and astrocytes, appears to be a common finding among many neurodegenerative disease models. Here we compare the effects of a retinal ischemia/reperfusion (I/R) injury on glial activation and neurodegeneration in wild type (WT) and C1qa-deficient mice in the retina and superior colliculus (SC). Retinal I/R was induced in mice through elevation of intraocular pressure to 120 mmHg for 60 min followed by reperfusion. Glial cell activation and population changes were assessed using immunofluorescence. Neuroprotection was determined using histological measurements of retinal layer thickness, RGC counts, and visual function by flash electroretinography (ERG).
RESULTS: Retinal I/R injury significantly upregulated C1q expression in the retina as early as 72 h and within 7 days in the superficial SC, and was sustained as long as 28 days. Accompanying increased C1q expression was activation of microglia and astrocytes as well as a significantly increased glial population density observed in the retina and SC. Microglial activation and changes in density were completely ablated in C1qa-deficient mice, interestingly however there was no effect on astrocytes. Furthermore, loss of C1qa significantly rescued I/R-induced loss of RGCs and protected against retinal layer thinning in comparison to WT mice. ERG assessment revealed early preservation of b-wave amplitude deficits from retinal I/R injury due to C1qa-deficiency that was lost by day 28.
CONCLUSIONS: Our results for the first time demonstrate the spatiotemporal changes in the neuroinflammatory response following retinal I/R injury at both local and distal sites of injury. In addition, we have shown a role for C1q as a primary mediator of microglial activation and pathological damage. This suggests developmental mechanisms of C1q may be re-engaged during injury response, modulation of which may be beneficial for neuroprotection.

PMID: 27008854 [PubMed - in process]

MIEN1, a novel interactor of Annexin A2, promotes tumor cell migration by enhancing AnxA2 cell surface expression.

Recent Research Articles from UNTHSC - Fri, 03/25/2016 - 06:29
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MIEN1, a novel interactor of Annexin A2, promotes tumor cell migration by enhancing AnxA2 cell surface expression.

Mol Cancer. 2015;14:156

Authors: Kpetemey M, Dasgupta S, Rajendiran S, Das S, Gibbs LD, Shetty P, Gryczynski Z, Vishwanatha JK

Abstract
BACKGROUND: Migration and invasion enhancer 1 (MIEN1) is a novel gene found to be abundantly expressed in breast tumor tissues and functions as a critical regulator of tumor cell migration and invasion to promote systemic metastases. Previous studies have identified post-translational modifications by isoprenylation at the C-terminal tail of MIEN1 to favor its translocation to the inner leaflet of plasma membrane and its function as a membrane-bound adapter molecule. However, the exact molecular events at the membrane interface activating the MIEN1-driven tumor cell motility are vaguely understood.
METHODS: MIEN1 was first studied using in-silico analysis on available RNA sequencing data of human breast tissues and its expression was ascertained in breast cells. We performed several assays including co-immunoprecipitation, wound healing, western blotting and immunofluorescence to decipher the molecular events involved in MIEN1-mediated tumor cell migration.
RESULTS: Clinically, MIEN1 is predominantly overexpressed in Her-2 and luminal B subtypes of breast tumors, and its increased expression correlates with poor disease free survival. Molecular studies identified a phosphorylation-dependent activation signal in the immunoreceptor tyrosine based activation motif (ITAM) of MIEN1 and the phosphorylation-deficient MIEN1-mutants (Y39F/50 F) to regulate filopodia generation, migration and invasion. We found that ITAM-phosphorylation of MIEN1 is significantly impaired in isoprenylation-deficient MIEN1 mutants indicating that prenylation of MIEN1 and membrane association is required for cross-phosphorylation of tyrosine residues. Furthermore, we identified MIEN1 as a novel interactor of Annexin A2 (AnxA2), a Ca(2+) -dependent phospholipid binding protein, which serves as an extracellular proteolytic center regulating plasmin generation. Fluorescence resonance energy transfer (FRET) confirmed that MIEN1 physically interacts with AnxA2 and functional studies revealed that they mutually cooperate to accentuate tumor cell motility. Interestingly, our study identified that ectopic overexpression of MIEN1 significantly enhances Tyr23-phosphorylation on AnxA2, thereby stimulating cell surface translocation of AnxA2 and catalyzing the activation of its proteolytic activity.
CONCLUSION: Our data show that the presence and interaction of both MIEN1 and AnxA2 in breast tumors are crucial drivers of cell motility. Our study has now deciphered a novel regulatory network governing the vicious process of breast tumor cell invasion-metastasis, and findings suggest MIEN1-AnxA2 as prospective targets to counter the deadly disease.

PMID: 26272794 [PubMed - indexed for MEDLINE]

Alcohol Withdrawal and Cerebellar Mitochondria.

Recent Research Articles from UNTHSC - Fri, 03/25/2016 - 06:29
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Alcohol Withdrawal and Cerebellar Mitochondria.

Cerebellum. 2015 Aug;14(4):421-37

Authors: Jung ME

Abstract
Cerebellar disorders trigger the symptoms of movement problems, imbalance, incoordination, and frequent fall. Cerebellar disorders are shown in various CNS illnesses including a drinking disorder called alcoholism. Alcoholism is manifested as an inability to control drinking in spite of adverse consequences. Human and animal studies have shown that cerebellar symptoms persist even after complete abstinence from drinking. In particular, the abrupt termination (ethanol withdrawal) of long-term excessive ethanol consumption has shown to provoke a variety of neuronal and mitochondrial damage to the cerebellum. Upon ethanol withdrawal, excitatory neurotransmitter molecules such as glutamate are overly released in brain areas including cerebellum. This is particularly relevant to the cerebellar neuronal network as glutamate signals are projected to Purkinje neurons through granular cells that are the most populated neuronal type in CNS. This excitatory neuronal signal may be elevated by ethanol withdrawal stress, which promotes an increase in intracellular Ca(2+) level and a decrease in a Ca(2+)-binding protein, both of which result in the excessive entry of Ca(2+) to the mitochondria. Subsequently, mitochondria undergo a prolonged opening of mitochondrial permeability transition pore and the overproduction of harmful free radicals, impeding adenosine triphosphate (ATP)-generating function. This in turn provokes the leakage of mitochondrial molecule cytochrome c to the cytosol, which triggers a cascade of adverse cytosol reactions. Upstream to this pathway, cerebellum under the condition of ethanol withdrawal has shown aberrant gene modifications through altered DNA methylation, histone acetylation, or microRNA expression. Interplay between these events and molecules may result in functional damage to cerebellar mitochondria and consequent neuronal degeneration, thereby contributing to motoric deficit. Mitochondria-targeting research may help develop a powerful new therapy to manage cerebellar disorders associated with hyperexcitatory CNS disorders like ethanol withdrawal.

PMID: 25195804 [PubMed - indexed for MEDLINE]

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