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1.  Oscillation of Clock and Clock Controlled Genes Induced by Serum Shock in Human Breast Epithelial and Breast Cancer Cells: Regulation by Melatonin 
This study investigates differences in expression of clock and clock-controlled genes (CCGs) between human breast epithelial and breast cancer cells and breast tumor xenografts in circadian intact rats and examines if the pineal hormone melatonin influences clock gene and CCG expression. Oscillation of clock gene expression was not observed under standard growth conditions in vitro, however, serum shock (50% horse serum for 2 h) induced oscillation of clock gene and CCG expression in MCF-10A cells, which was repressed or disrupted in MCF-7 cells. Melatonin administration following serum shock differentially suppressed or induced clock gene (Bmal1 and Per2) and CCG expression in MCF10A and MCF-7 cells. These studies demonstrate the lack of rhythmic expression of clock genes and CCGs of cells in vitro and that transplantation of breast cancer cells as xenografts into circadian competent hosts re-establishes a circadian rhythm in the peripheral clock genes of tumor cells.
doi:10.4137/BCBCR.S9673
PMCID: PMC3448497  PMID: 23012497
melatonin; clock genes; circadian; serum shock; breast cancer
2.  Differences in stroke outcome based on sex 
Neurology  2010;74(9):767-771.
Objective:
Stroke thrombolysis may have a differential effect by sex. We sought to examine the relationship between sex and outcome after thrombolysis.
Methods:
This is a retrospective cohort study of stroke patients from the Registry of Canadian Stroke Network phase 1 (June 2001-February 2002) and phase 2 (June 2002-December 2002). Variables including demographics, history, clinical data, process measures, and outcome were analyzed. The primary outcomes were the Stroke Impact Scale-16 score (SIS-16) and mortality at 6 months. We compared the outcomes of the thrombolyzed and nonthrombolyzed cohorts and examined the data for a tissue plasminogen activator (tPA)-by-sex interaction on the 2 primary outcomes.
Results:
The overall proportion of patients who achieved an excellent outcome (SIS-16 >75) was not different by gender. However, the proportion of patients achieving an excellent outcome in the non-tPA cohort was much greater in males, with an absolute risk difference of 11.8%. A multiplicative treatment by sex interaction was evident (p = 0.054). This interaction was not present for stroke case fatality.
Conclusions:
Women fared poorly compared to men in the placebo groups, but this negative prognostic sex effect was neutralized by thrombolysis.
GLOSSARY
= modified Rankin Score;
= Registry of the Canadian Stroke Network;
= Stroke Impact Scale-16 score;
= tissue plasminogen activator.
doi:10.1212/WNL.0b013e3181d5275c
PMCID: PMC2836873  PMID: 20194917
3.  A sequential treatment regimen with melatonin and all-trans retinoic acid induces apoptosis in MCF-7 tumour cells. 
British Journal of Cancer  1998;77(12):2129-2137.
Neoplastic events are marked by uncontrolled cell proliferation. One major focus of cancer research has been to identify treatments that reduce or inhibit cell growth. Over the years, various compounds, both naturally occurring and chemically synthesized, have been used to inhibit neoplastic cell proliferation. Two such oncostatic agents, melatonin and retinoic acid, have been shown to suppress the growth of hormone-responsive breast cancer. Currently, separate clinical protocols exist for the administration of retinoids and melatonin as adjuvant therapies for cancer. Using the oestrogen receptor (ER)-positive MCF-7 human breast tumour cell line, our laboratory has studied the effects of a sequential treatment regimen of melatonin followed by all-trans retinoic acid (atRA) on breast tumour cell proliferation in vitro. Incubation of hormonally responsive MCF-7 and T47D cells with melatonin (10(-9) M) followed 24 h later by atRA (10(-9) M) resulted in the complete cessation of cell growth as well as a reduction in the number of cells to below the initial plating density. This cytocidal effect is in contrast to the growth-suppressive effects seen with either hormone alone. This regimen of melatonin followed by atRA induced cytocidal effects on MCF-7 cells by activating pathways leading to apoptosis (programmed cell death) as evidenced by decreased ER and Bcl-2 and increased Bax and transforming growth factor beta 1 (TGF-beta1) expression. Apoptosis was reflected morphologically by an increase in the number of lysosomal bodies and perinuclear chromatin condensation, cytoplasmic blebbing and the presence of apoptotic bodies. The apoptotic effect of this sequential treatment with melatonin and atRA appears to be both cell and regimen specific as (a) ER-negative MDA-MB-231 and BT-20 breast tumour cells were unaffected, and (b) the simultaneous administration of melatonin and atRA was not associated with apoptosis in any of the breast cancer cell lines studied. Taken together, the results suggest that use of an appropriate regimen of melatonin and atRA should be considered for preclinical and clinical evaluation against ER-positive human breast cancer.
Images
PMCID: PMC2150391  PMID: 9649124
5.  Bacteria and the aetiology of cancer of the large bowel. 
Gut  1969;10(5):334-335.
PMCID: PMC1552859  PMID: 5771664
7.  Does a fall prevention educational programme improve knowledge and change exercise prescribing behaviour in health and exercise professionals? A study protocol for a randomised controlled trial 
BMJ Open  2014;4(11):e007032.
Introduction
Falling in older age is a serious and costly problem. At least one in three older people fall annually. Although exercise is recognised as an effective fall prevention intervention, low numbers of older people engage in suitable programmes. Health and exercise professionals play a crucial role in addressing fall risk in older adults. This trial aims to evaluate the effect of participation in a fall prevention educational programme, compared with a wait-list control group, on health and exercise professionals’ knowledge about fall prevention and the effect on fall prevention exercise prescription behaviour and confidence to prescribe the exercises to older people.
Methods and analysis
A randomised controlled trial involving 220 consenting health and exercise professionals will be conducted. Participants will be individually randomised to an intervention group (n=110) to receive an educational workshop plus access to internet-based support resources, or a wait-list control group (n=110). The two primary outcomes, measured 3 months after randomisation, are: (1) knowledge about fall prevention and (2) self-perceived change in fall prevention exercise prescription behaviour. Secondary outcomes include: (1) participants’ confidence to prescribe fall prevention exercises; (2) the proportion of people aged 60+ years seen by trial participants in the past month who were prescribed fall prevention exercise; and (3) the proportion of fall prevention exercises prescribed by participants to older people in the past month that comply with evidence-based guidelines. Outcomes will be measured with a self-report questionnaire designed specifically for the trial.
Ethics and dissemination
The trial protocol was approved by the Human Research Ethics Committee, The University of Sydney, Australia. Trial results will be disseminated via peer reviewed journals, presentations at international conferences and participants’ newsletters.
Trial registration number
Trial protocol was registered with the Australian and New Zealand Clinical Trials Registry (Number ACTRN12614000224628) on 3 March 2014.
doi:10.1136/bmjopen-2014-007032
PMCID: PMC4244414  PMID: 25410607
EDUCATION & TRAINING (see Medical Education & Training); GERIATRIC MEDICINE; PREVENTIVE MEDICINE
8.  Quantitative proteomics of delirium cerebrospinal fluid 
Translational Psychiatry  2014;4(11):e477-.
Delirium is a common cause and complication of hospitalization in older people, being associated with higher risk of future dementia and progression of existing dementia. However relatively little data are available on which biochemical pathways are dysregulated in the brain during delirium episodes, whether there are protein expression changes common among delirium subjects and whether there are any changes which correlate with the severity of delirium. We now present the first proteomic analysis of delirium cerebrospinal fluid (CSF), and one of few studies exploring protein expression changes in delirium. More than 270 proteins were identified in two delirium cohorts, 16 of which were dysregulated in at least 8 of 17 delirium subjects compared with a mild Alzheimer's disease neurological control group, and 31 proteins were significantly correlated with cognitive scores (mini-mental state exam and acute physiology and chronic health evaluation III). Bioinformatics analyses revealed expression changes in several protein family groups, including apolipoproteins, secretogranins/chromogranins, clotting/fibrinolysis factors, serine protease inhibitors and acute-phase response elements. These data not only provide confirmatory evidence that the inflammatory response is a component of delirium, but also reveal dysregulation of protein expression in a number of novel and unexpected clusters of proteins, in particular the granins. Another surprising outcome of this work is the level of similarity of CSF protein profiles in delirium patients, given the diversity of causes of this syndrome. These data provide additional elements for consideration in the pathophysiology of delirium as well as potential biomarker candidates for delirium diagnosis.
doi:10.1038/tp.2014.114
PMCID: PMC4259987  PMID: 25369144
9.  Mutations in the Highly Conserved SLQYLA Motif of Vif in a Simian-Human Immunodeficiency Virus Result in a Less Pathogenic Virus and is Associated with G-to-A Mutations in the Viral Genome 
Virology  2008;383(2):362-372.
The simian-human immunodeficiency virus (SHIV)/macaque model for human immunodeficiency virus type 1 has become a useful tool to assess the role of accessory genes in lentiviral pathogenesis. In this study, we introduced two amino acid changes in the highly conserved SLQYLA domain (to AAQYLA) of the SIV Vif protein. The resulting virus, SHIVVifAAQYLA, was used to infect three macaques, which were followed for over six months. Plasma viral loads and circulating CD4+ T cell levels were assessed during the course of infection. The three macaques inoculated with SHIVVifAAQYLA did not develop significant CD4+ T cell loss over the course of their infection, had plasma viral RNA loads that were over 100-fold lower than macaques inoculated with parental SHIVKU-1bMC33, and developed no histological lesions in lymphoid tissues. DNA and RT-PCR analysis revealed that only a select number of tissues were infected with this virus. Sequence analysis indicates that the site-directed changes were stable during the first three weeks after inoculation but thereafter the S147A amino acid substitution changed to a threonine in two of three macaques. The L148A substitution remained stable in the vif amplified from the PBMC of all three macaques. Sequence analysis of vif, vpu, env and nef genes revealed G-to-A mutations in the genes amplified from macaques inoculated with SHIVVifAAQYLA, which were higher than in a macaque inoculated with parental SHIVKU-1bMC33. We found that the majority (>85%) of the G-to-A mutations were in the context of 5′-TC (minus strand) and not 5′-CC, suggestive that one or more of the rhesus APOBEC3 proteins may be responsible for the observed mutational patterns with rhesus APOBEC3G for a minority of the mutations since its GG-to-AG mutational pattern was infrequently detected. Finally, macaques inoculated with SHIVVifAAQYLA developed immunoprecipitating antibody responses against the virus. The results from this study provide the first in vivo evidence of the importance of the SLQYLA domain in viral pathogenesis and show that targeted mutations in vif can lead to a persistent infection with G-to-A changes accumulating in the viral genome.
doi:10.1016/j.virol.2008.10.013
PMCID: PMC4104693  PMID: 19027134
10.  BST-2 Mediated Restriction of Simian-Human Immunodeficiency Virus 
Virology  2010;406(2):312-321.
Pathogenic simian-human immunodeficiency viruses (SHIV)contain HIV-1 Vpu and SIV Nef, both shown to counteract BST-2 (HM1.24; CD317; tetherin) inhibition of virus release in a species-specific manner. We show that human and pig-tailed BST-2 (ptBST-2) restrict SHIV. We found that sequential “humanize” of the transmembrane domain (TMD) of the pig-tailed BST-2 (ptBST-2) protein resulted in a fluctuation in sensitivity to HIV-1 Vpu. Our results also show that the length of the TMD in human and ptBST-2 proteins is important for BST-2 restriction and susceptibility to Vpu. Taken together, our results emphasize the importance of tertiary structure in BST-2 antagonism and suggests that the HIV-1 Vpu transmembrane domain may have additional functions in vivo unrelated to BST-2 antagonism.
doi:10.1016/j.virol.2010.07.021
PMCID: PMC4104713  PMID: 20708210
11.  Membrane Raft Association of the Vpu Protein of Human Immunodeficiency Virus Type 1 Correlates with Enhanced Virus Release 
Virology  2010;408(1):89-102.
The Vpu protein of human immunodeficiency virus type 1 (HIV-1) is known to enhance virion release from certain cell types. To accomplish this function, Vpu interacts with the restriction factor known as bone marrow stromal cell antigen 2 (BST-2)/tetherin. In this study, we analyzed whether the Vpu protein is associated with microdomains known as lipid or membrane rafts. Our results indicate that Vpu partially partitions into detergent resistant membrane (DRM) fractions when expressed alone or in the context of simian-human immunodeficiency virus (SHIV) infection. The ability to be partitioned into rafts was observed with both subtype B and C Vpu proteins. The use of cholesterol lowering lovastatin/M-β-cyclodextrin and co-patching experiments confirmed that Vpu can be detected in cholesterol rich regions of membranes. Finally, we present data showing that raft association-defective transmembrane mutants of Vpu have impaired enhanced virus release function, but still maintain the ability to down-regulate CD4.
doi:10.1016/j.virol.2010.08.031
PMCID: PMC4104719  PMID: 20880565
12.  Identification of Amino Acids within the Second Alpha Helical Domain of the Human Immunodeficiency Virus type 1 Vpu that are Critical for Preventing CD4 Cell Surface Expression 
Virology  2009;397(1):104-112.
Human immunodeficiency virus type 1 (HIV-1) encodes for a Vpu protein, which interacts with CD4 resulting in its degradation. In this study, we examined the role of the ten amino acids within the predicted second α-helical domain of the subtype B Vpu cytoplasmic tail in CD4 down-modulation using a VpuEGFP reporter system. Our findings indicate that the invariant leucine at position 63 and, to a lesser extent, the valine at position 68 were required for CD4 down-modulation. Mutation of analogous L63 in Vpu proteins subtypes A2, B, C, D, and H also abolished CD4 down-modulation from the cell surface. Co-immunoprecipitation analysis revealed that L63A and V68A mutants were capable of binding CD4 and still retained the ability to interact with h-β-TrCP1. Taken together, these results indicate that amino acid substitutions in the second α-helical domain that retain the predicted structure and binding to h-β-TrCP1 can influence Vpu-mediated CD4 degradation.
doi:10.1016/j.virol.2009.10.048
PMCID: PMC4104991  PMID: 19944437
13.  Requirements of the Membrane Proximal Tyrosine and Dileucine Based Sorting Signals for Efficient Transport of the Subtype C Vpu Protein to the Plasma Membrane and in Virus Release 
Virology  2008;378(1):58-68.
Previously, we showed that the Vpu protein from HIV-1 subtype C is more efficiently transported to the cell surface than the well studied subtype B Vpu (Pacyniak et al., 2005) and that a SHIV expressing the subtype C Vpu exhibited a decreased rate of CD4+ T-cell loss following inoculation in macaques (Hill et al., 2007). In this study, we examined the role of overlapping tyrosine-based (YXXM) and dileucine-based ([D/E]XXXL[L/I]) motifs in the membrane proximal region of the subtype C Vpu (EYRKLL) in Vpu intracellular transport, CD4 surface expression and virus release from the cell surface. We constructed three site-directed mutants of the subtype C vpu and fused these genes to the gene for enhanced green fluorescent protein (EGFP). The first mutation made altered the tyrosine (EARKLL; VpuSCEGFPY35A), the second altered the dileucine motif (EYRKLG; VpuSCEGFPL39G), and the third contained both amino acid substitutions (EARKLG; VpuSCEGFPYL35,39AG) in this region of the Vpu protein. The VpuSCEGFPY35A protein was transported to the cell surface similar to the unmodified VpuSCEGFP1 while VpuSCEGFPL39G was expressed at the cell surface at significantly reduced levels. The VpuSCEGFPYL35,39AG was found to have an intermediate level of cell surface expression. All three mutant Vpu proteins were analyzed for the ability to prevent cell surface expression of CD4. We found that both single mutants did not significantly effect at CD4 surface expression while the double mutant (VpuSCEGFPYL35,39AG) was significantly less efficient at preventing cell surface CD4 expression. Chimeric simian-human immunodeficiency viruses were constructed with theses mutations in vpu (SHIVSCVpuY35A, SHIVSCVpuL39G and SHIVSCVpuYL35,39AG). Our results indicate that SHIVSCVpuL39G replicated much more efficiently and was much more cytopathic than SHIVSCVpu. In contrast, SHIVSCVpuY35A and SHIVSCVpuYL35,39AG replicated less efficiently when compared to the parental SHIVSCVpu. Taken together, these results show for the first time that the tyrosine-based sorting motif in the cytoplasmic domain of Vpu is essential for efficient virus release. These results also indicate that the dileucine-based sorting motif affects the intracellular trafficking of clade C Vpu proteins, virus replication, and release.
doi:10.1016/j.virol.2008.05.022
PMCID: PMC4104992  PMID: 18579178
14.  Upregulation of CB1 receptor binding in the ventromedial prefrontal cortex promotes proactive stress-coping strategies following chronic stress exposure 
Behavioural brain research  2012;237:333-337.
Accumulating evidence has revealed that dysregulation of the endocannabinoid system could contribute to the development of major depression. Studies carried out post-mortem in depressed suicide victims have revealed increased CB1 receptor binding site density in the prefrontal cortex (PFC). Accordingly, exposure of rodents to chronic unpredictable stress (CUS) results in phenotypic changes that mirror those of human depression, including increased CB1 receptor binding site density in the PFC. Our goal in these studies was to examine the effects of CUS on the density of CB1 receptor binding sites in the rodent medial PFC and to explore the role of this alteration in the behavioral changes invoked by CUS. Rodents exposed to CUS exhibited increased CB1 receptor maximal binding site density (Bmax) within the ventromedial PFC, but not the dorsomedial PFC. To determine whether this change in the ventromedial PFC is an adaptive response, or alternatively, a consequence of chronic stress that contributes to the adoption of passive coping, we examined whether local CB1 receptor blockade within the ventromedial PFC following CUS would significantly alter behaviors in the forced swim test (FST). CUS exposure significantly increased passive coping in the FST, and this was further augmented by discrete ventromedial PFC microinfusions of the CB1 receptor antagonist AM251 prior to swim stress. Moreover, local CB1 receptor blockade reduced active coping responses in CUS-exposed rats. These findings suggest that the increase in CB1 receptor Bmax observed in the ventromedial PFC of rodents exposed to CUS maintains proactive coping strategies following chronic stress exposure.
doi:10.1016/j.bbr.2012.09.053
PMCID: PMC3501995  PMID: 23047058
CB1 receptor; ventromedial prefrontal cortex; chronic unpredictable stress; forced swim test; microinfusion
15.  Revisiting the ultra-high dose rate effect: implications for charged particle radiotherapy using protons and light ions 
The British Journal of Radiology  2012;85(1018):e933-e939.
Objective
To reinvestigate ultra-high dose rate radiation (UHDRR) radiobiology and consider potential implications for hadrontherapy.
Methods
A literature search of cellular UHDRR exposures was performed. Standard oxygen diffusion equations were used to estimate the time taken to replace UHDRR-related oxygen depletion. Dose rates from conventional and novel methods of hadrontherapy accelerators were considered, including spot scanning beam delivery, which intensifies dose rate.
Results
The literature findings were that, for X-ray and electron dose rates of around 109 Gy s–1, 5–10 Gy depletes cellular oxygen, significantly changing the radiosensitivity of cells already in low oxygen tension (around 3 mmHg or 0.4 kPa). The time taken to reverse the oxygen depletion of such cells is estimated to be over 20–30 s at distances of over 100 μm from a tumour blood vessel. In this time window, tumours have a higher hypoxic fraction (capable of reducing tumour control), so the next application of radiation within the same fraction should be at a time that exceeds these estimates in the case of scanned beams or with ultra-fast laser-generated particles.
Conclusion
This study has potential implications for particle therapy, including laser-generated particles, where dose rate is greatly increased. Conventional accelerators probably do not achieve the critical UHDRR conditions. However, specific UHDRR oxygen depletion experiments using proton and ion beams are indicated.
doi:10.1259/bjr/17827549
PMCID: PMC3474025  PMID: 22496068
16.  Offering fragile X syndrome carrier screening: a prospective mixed-methods observational study comparing carrier screening of pregnant and non-pregnant women in the general population 
BMJ Open  2013;3(9):e003660.
Introduction
Fragile X syndrome (FXS) is the leading cause of inherited intellectual and developmental disability. Policy development relating to carrier screening programmes for FXS requires input from large studies examining not only test uptake but also psychosocial aspects. This study will compare carrier screening in pregnant and non-pregnant populations, examining informed decision-making, psychosocial issues and health economics.
Methods and Analysis
Pregnant and non-pregnant women are being recruited from general practices and obstetric services. Women receive study information either in person or through clinic mail outs. Women are provided pretest counselling by a genetic counsellor and make a decision about testing in their own time. Data are being collected from two questionnaires: one completed at the time of making the decision about testing and the second 1 month later. Additional data are gathered through qualitative interviews conducted at several time points with a subset of participating women, including all women with a positive test result, and with staff from recruiting clinics. A minimum sample size of 500 women/group has been calculated to give us 88% power to detect a 10% difference in test uptake and 87% power to detect a 10% difference in informed choice between the pregnant and non-pregnant groups. Questionnaire data will be analysed using descriptive statistics and multivariate logistic regression models. Interview data will be thematically analysed. Willingness-to-pay and cost effectiveness analyses will also be performed. Recruitment started in July 2009 and data collection will be completed by December 2013.
Ethics and Dissemination
Ethics approval has been granted by the Universities of Melbourne and Western Australia and by recruiting clinics, where required. Results will be reported in peer-reviewed publications, conference presentations and through a website http://www.fragilexscreening.net.au. The results of this study will make a significant contribution to discussions about the wider introduction of population carrier screening for FXS.
doi:10.1136/bmjopen-2013-003660
PMCID: PMC3773647  PMID: 24022395
Genetics; Public Health
17.  A randomised study evaluating the use of pyridoxine to avoid capecitabine dose modifications 
British Journal of Cancer  2012;107(4):585-587.
Background:
Pyridoxine is frequently used to treat capecitabine-induced hand–foot syndrome (HFS), although the evidence of benefit is lacking. We performed a randomised placebo-controlled trial to determine whether pyridoxine could avoid the need for capecitabine dose modifications and improve outcomes.
Methods:
A total of 106 patients planned for palliative single-agent capecitabine (53 in each arm, 65%/ 35% colorectal/breast cancer) were randomised to receive either concomitant pyridoxine (50 mg po) or matching placebo three times daily.
Results:
Compared with placebo, pyridoxine use was associated with an increased rate of avoiding capecitabine dose modifications (37% vs 23%, relative risk 0.59, 95% CI 0.29, 1.20, P=0.15) and fewer grade 3/4 HFS-related adverse events (9% vs 17%, odds ratio 0.51, 95% CI 0.15–1.6, P=0.26). Use of pyridoxine did not improve response rate or progression-free survival.
Conclusion:
Pyridoxine may reduce the need for capecitabine dose modifications and the incidence of severe HFS, but does not impact on antitumour effect.
doi:10.1038/bjc.2012.318
PMCID: PMC3419962  PMID: 22814578
capecitabine; pyridoxine; hand–foot syndrome; randomised trial
18.  CHRONIC, NONINVASIVE GLUCOCORTICOID ADMINISTRATION SUPPRESSES LIMBIC ENDOCANNABINOID SIGNALING IN MICE 
Neuroscience  2011;204:83-89.
Limbic endocannabinoid signaling is known to be sensitive to chronic stress; however, studies investigating the impact of prolonged exposure to glucocorticoid hormones have been limited by the concurrent exposure to the stress of daily injections. The present study was designed to examine the effects of a noninvasive approach to alter plasma corticosterone (CORT) on the endocannabinoid system. More precisely, we explored the effects of a 4-week exposure to CORT dissolved in the drinking water of mice (100 μg/ml) and measured cannabinoid CB1 receptor binding, endocannabinoid content, activity of the endocannabinoid degrading enzyme free fatty acid amide hydrolase (FAAH), and mRNA expression of both the CB1 receptor and FAAH in both the hippocampus and amygdala. Our data demonstrate that CORT decreases CB1 receptor binding site density in both the hippocampus and amygdala and also reduced anandamide (AEA) content and increased FAAH activity within both structures. These changes in both CB1 receptor binding and FAAH activity were not accompanied by changes in mRNA expression of either the CB1 receptor or FAAH in either brain region. Interestingly, our CORT delivery regimen significantly increased 2-AG concentrations within the hippocampus, but not the amygdala. Collectively, these data demonstrate that the confounder of injection stress is sufficient to conceal the ability of protracted exposure to glucocorticoids to reduce CB1 receptor density and augment AEA metabolism within limbic structures.
doi:10.1016/j.neuroscience.2011.08.048
PMCID: PMC3697830  PMID: 21939741
19.  Vegetarian diet-induced increase in linoleic acid in serum phospholipids is associated with improved insulin sensitivity in subjects with type 2 diabetes 
Nutrition & Diabetes  2013;3(6):e75-.
BACKGROUND AND AIMS:
Fatty acids are important cellular constituents that may affect many metabolic processes relevant for the development of diabetes and its complications. We showed previously that vegetarian diet leads to greater increase in metabolic clearance rate of glucose (MCR) than conventional hypocaloric diet. The aim of this secondary analysis was to explore the role of changes in fatty acid composition of serum phospholipids in diet- and exercise-induced changes in MCR in subjects with type 2 diabetes (T2D).
METHODS:
Subjects with T2D (n=74) were randomly assigned into a vegetarian group (VG, n=37) following vegetarian diet or a control group (CG, n=37) following a conventional diet. Both diets were calorie restricted (−500 kcal day–1). Participants were examined at baseline, 12 weeks of diet intervention and 24 weeks (subsequent 12 weeks of diet were combined with aerobic exercise). The fatty acid composition of serum phospholipids was measured by gas liquid chromatography. MCR was measured by hyperinsulinemic isoglycemic clamp. Visceral fat (VF) was measured by magnetic resonance imaging.
RESULTS:
Linoleic acid (LA; 18:2n6) increased in VG (P=0.04), whereas it decreased in CG (P=0.04) in response to dietary interventions. It did not change significantly after the addition of exercise in either group (group × time P<0.001). In VG, changes in 18:2n6 correlated positively with changes in MCR (r=+0.22; P=0.04) and negatively with changes in VF (r=−0.43; P=0.01). After adjustment for changes in body mass index, the association between 18:2n6 and MCR was no longer significant. The addition of exercise resulted in greater changes of phospholipid fatty acids composition in VG than in CG.
CONCLUSION:
We demonstrated that the insulin-sensitizing effect of a vegetarian diet might be related to the increased proportion of LA in serum phospholipids.
doi:10.1038/nutd.2013.12
PMCID: PMC3697401  PMID: 23775014
fatty acid composition of serum phospholipids; insulin resistance; linoleic acid; type 2 diabetes; vegetarian diet; visceral fat
20.  Fatty Acid Composition of Adipose Tissue Triglycerides After Weight Loss and Weight Maintenance: the DIOGENES Study 
Summary
Fatty acid composition of adipose tissue changes with weight loss. Palmitoleic acid as a possible marker of endogenous lipogenesis or its functions as a lipokine are under debate. Objective was to assess the predictive role of adipose triglycerides fatty acids in weight maintenance in participants of the DIOGENES dietary intervention study. After an 8-week low calorie diet (LCD) subjects with > 8 % weight loss were randomized to 5 ad libitum weight maintenance diets for 6 months: low protein (P)/low glycemic index (GI) (LP/LGI), low P/high GI (LP/HGI), high P/low GI (HP/LGI), high P/high GI (HP/HGI), and a control diet. Fatty acid composition in adipose tissue triglycerides was determined by gas chromatography in 195 subjects before the LCD (baseline), after LCD and weight maintenance. Weight change after the maintenance phase was positively correlated with baseline adipose palmitoleic (16:1n-7), myristoleic (14:1n-5) and trans-palmitoleic acid (16:1n-7t). Negative correlation was found with baseline oleic acid (18:1n-9). Lower baseline monounsaturated fatty acids (14:1n-5, 16:1n-7 and trans 16:1n-7) in adipose tissue triglycerides predict better weight maintenance. Lower oleic acid predicts lower weight decrease. These findings suggest a specific role of monounsaturated fatty acids in weight management and as weight change predictors.
PMCID: PMC3594990  PMID: 23098653
Diet; Palmitoleic acid; Fatty acids; Adipose tissue; Obesity management
21.  Endocannabinoid Signaling, Glucocorticoid-Mediated Negative Feedback and Regulation of the HPA Axis 
Neuroscience  2011;204:5-16.
The hypothalamic-pituitary-adrenal (HPA) axis regulates the outflow of glucocorticoid hormones under basal conditions and in response to stress. Within the last decade, a large body of evidence has mounted indicating that the endocannabinoid system is involved in the central regulation of the stress response; however, the specific role endocannabinoid signalling plays in phases of HPA axis regulation, or the neural sites of action mediating this regulation, was not mapped out until recently. This review aims to collapse the current state of knowledge regarding the role of the endocannabinoid system in the regulation of the HPA axis to put together a working model of how and where endocannabinoids act within the brain to regulate outflow of the HPA axis. Specifically, we discuss the role of the endocannabinoid system in the regulation of the HPA axis under basal conditions, activation in response to acute stress and glucocorticoid-mediated negative feedback. Interestingly, there appears to be some anatomical specificity to the role of the endocannabinoid system in each phase of HPA axis regulation, as well as distinct roles of both anandamide and 2-arachidonoylglycerol in these phases. Ultimately, the current level of information indicates that endocannabinoid signalling acts to suppress HPA axis activity through concerted actions within the prefrontal cortex, amygdala and hypothalamus.
doi:10.1016/j.neuroscience.2011.12.030
PMCID: PMC3288468  PMID: 22214537
22.  Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain 
Neurobiology of Aging  2006;28(10):1493-1506.
Aged individuals with Down syndrome (DS) develop Alzheimer's disease (AD) neuropathology by the age of 40 years. The purpose of the current study was to measure age-associated changes in APP processing in 36 individuals with DS (5 months–69 years) and in 26 controls (5 months–100 years). Alpha-secretase significantly decreased with age in DS, particularly in cases over the age of 40 years and was stable in controls. The levels of C-terminal fragments of APP reflecting alpha-secretase processing (CTF-alpha) decreased with age in both groups. In both groups, there was significant increase in beta-secretase activity with age. CTF-beta remained constant with age in controls suggesting compensatory increases in turnover/clearance mechanisms. In DS, young individuals had the lowest CTF-beta levels that may reflect rapid conversion of beta-amyloid (Aβ) to soluble pools or efficient CTF-beta clearance mechanisms. Treatments to slow or prevent AD in the general population targeting secretase activity may be more efficacious in adults with DS if combined with approaches that enhance Aβ degradation and clearance.
doi:10.1016/j.neurobiolaging.2006.06.023
PMCID: PMC3375834  PMID: 16904243
Alzheimer's disease; Beta-amyloid; Oldest old; Trisomy 21
23.  Achieving Faster Recanalization Times by IA Thrombolysis in Acute Ischemic Stroke: Where Should We Direct Our Efforts? 
Interventional Neuroradiology  2011;17(2):228-234.
Summary
Faster recanalization correlates with better outcomes in acute ischemic stroke. We analyzed times from arrival in ER to end of treatment in patients undergoing endovascular treatment for acute ischemic stroke at our institution.
We retrospectively studied patients who underwent IA procedures for stroke from 2005 to 2009 noting the times of arrival to ER, CT scan, arrival to DSA, arterial puncture and recanalization from our endovascular database. A subgroup analysis was performed based on administration of GA, use of mechanical devices and whether the procedure was performed during regular hours or after hours.
Of 101 patients, 53 were male, with a median age of 66 years (range 18-87). There were 81 anterior circulation strokes. Median ER to CT time was 22 min (2-1025), CT to DSA arrival time 80 min (range 4-990), DSA arrival to puncture time 24 min (range 0-75) and puncture to recanalization time 84 min (range 11-206). 23.3% of patients had an ER to CT time interval of > 60 min and 71.3 % had a CT to DSA time interval of > 60 min contributing to significant in-hospital delays. For subgroup analysis the Mann-Whitney test was used. No significant differences in CT to DSA arrival (p=0.8), DSA arrival to puncture (p=0.1) and puncture to recanalization (p=0.59) times were noted between patients with and without GA. No significant difference was noted in puncture to recanalization times with or without device (p=0.78). 39 cases were done during regular (R) hours and 62 after (A) hours. Median ER to CT time (R=18 min, A = 27 min, p 0.02), CT to DSA arrival time (R=64 min, A=90 min, p 0.004) and DSA arrival to puncture time (R=18 min, A=25 min, p 0.003) was significantly higher after hours.
ER to CT and CT to DSA arrival times in patients undergoing endovascular stroke therapy show wide variability and therefore, considerable scope for reduction. Time differences during regular and after hours should serve as a reminder to make efforts to reduce overall ischemic times in spite of staffing patterns and resource availability.
PMCID: PMC3287276  PMID: 21696664
stroke, thrombolysis, recanalization, tPA
24.  Combined acoustic and optical trapping 
Biomedical Optics Express  2011;2(10):2859-2870.
Combining several methods for contact free micro-manipulation of small particles such as cells or micro-organisms provides the advantages of each method in a single setup. Optical tweezers, which employ focused laser beams, offer very precise and selective handling of single particles. On the other hand, acoustic trapping with wavelengths of about 1 mm allows the simultaneous trapping of many, comparatively large particles. With conventional approaches it is difficult to fully employ the strengths of each method due to the different experimental requirements. Here we present the combined optical and acoustic trapping of motile micro-organisms in a microfluidic environment, utilizing optical macro-tweezers, which offer a large field of view and working distance of several millimeters and therefore match the typical range of acoustic trapping. We characterize the acoustic trapping forces with the help of optically trapped particles and present several applications of the combined optical and acoustic trapping, such as manipulation of large (75 μm) particles and active particle sorting.
doi:10.1364/BOE.2.002859
PMCID: PMC3190962  PMID: 22025990
(140.7010) Laser trapping; (170.4520) Optical confinement and manipulation; (350.4855) Optical tweezers or optical manipulation; (110.7170) Ultrasound
25.  Comparison of the Replication and Persistence of Simian-Human Immunodeficiency Viruses Expressing Vif Proteins with Mutation of the SLQYLA or HCCH Domains in Macaques 
Virology  2010;404(2):187-203.
The Vif protein of primate lentiviruses interacts with APOBEC3 proteins, which results in shunting of the APOBEC3-Vif complex to the proteosome for degradation. Using the simian-human immunodeficiency virus (SHIV)/macaque model, we compared the replication and pathogenicity of SHIVs that express a Vif protein in which the entire SLQ(Y/F)LA (SHIVVif5A) or HCCH (SHIVVifHCCH(−)) domains were substituted with alanine residues. Each virus was inoculated into three macaques and various viral and immunological parameters followed for six months. All macaques maintained stable circulating CD4+ T cells, developed low viral loads, maintained the engineered mutations, yielded no histological lesions, and developed immunoprecipitating antibodies early post-inoculation. Sequence analysis of nef and vpu from three lymphoid tissues revealed a high percentage of G-to-A-substitutions. Our results show that while the presence of HCCH and SLQ(Y/F)LA domains are critical in vivo, there may exist APOBEC3 negative reservoirs that allow for low levels of viral replication and persistence but not disease.
doi:10.1016/j.virol.2010.04.017
PMCID: PMC2974619  PMID: 20627348

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