Publications by authors named "Helen Tang"

18 Publications

  • Page 1 of 1

Female Sex Is Associated with Improved Long-Term Survival Following Allogeneic Hematopoietic Stem Cell Transplantation.

Transplant Cell Ther 2021 Jun 17. Epub 2021 Jun 17.

Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Durham, North Carolina. Electronic address:

Life expectancy for long-term survivors of allogeneic hematopoietic stem cell transplantation (alloHSCT), defined as those living ≥5 years post-transplantation, is significantly lower compared with that of the age-matched general population despite a relatively low primary disease relapse rate at >2 years post-transplantation. Among several factors, patient sex is increasingly recognized as a prognostic indicator of long-term survival. We examined the influence of patient sex and donor-recipient sex matching on overall survival (OS) in a landmark analysis of long-term survivors. Using our institutional database supplemented with individual patient record review, we retrospectively investigated the relative influence of recipient sex and donor-recipient sex matching on outcomes of long-term survivors of alloHSCT between 1994 and 2014. Over this 20-year period, 247 met inclusion criteria for analysis; males and females had similar demographic and treatment characteristics. However, significantly more deaths after the 5-year landmark occurred in male recipients. Interestingly, donor sex did not have a significant impact on OS in multivariate analysis, and differences in OS of donor-recipient sex pairs was driven by recipient sex. In addition to recipient sex, only chronic graft-versus-host disease (cGVHD) retained significance as a covariate with an impact on OS in multivariate analysis. Men experienced slightly higher, but statistically nonsignificant, rates and increased severity of cGVHD, and had higher cGVHD-related mortality compared with females. In this long-term survival analysis of adult alloHSCT recipients, one of the only to include follow-up to 15 years, our results show that women survive significantly longer than men irrespective of their age at transplantation. This outcome is independent of other common pretransplantation prognostic indicators, such as donor sex or performance status at transplantation. The inferior survival in males is consistent with survival outcomes described in the transplantation literature. Increasing evidence suggests a biological basis for long-term sex-determined outcomes, possibly owing to differing rates or severity of cGVHD or sustained alloimmune tolerance in females. Larger studies are warranted to validate these retrospective clinical results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.06.012DOI Listing
June 2021

Decreased Mortality in 1-Year Survivors of Umbilical Cord Blood Transplant vs. Matched Related or Matched Unrelated Donor Transplant in Patients with Hematologic Malignancies.

Transplant Cell Ther 2021 08 12;27(8):669.e1-669.e8. Epub 2021 May 12.

Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University, Durham, North Carolina. Electronic address:

Allogeneic hematopoietic stem cell transplantation (HCT) has the potential to cure hematologic malignancies but is associated with significant morbidity and mortality. Although deaths during the first year after transplantation are often attributable to treatment toxicities and complications, death after the first year may be due to sequelae of accelerated aging caused by cellular senescence. Cytotoxic therapies and radiation used in cancer treatments and conditioning regimens for HCT can induce aging at the molecular level; HCT patients experience time-dependent effects, such as frailty and aging-associated diseases, more rapidly than people who have not been exposed to these treatments. Consistent with this, recipients of younger cells tend to have decreased markers of aging and improved survival, decreased graft-versus-host disease, and lower relapse rates. Given that umbilical cord blood (UCB) is the youngest donor source available, we studied the outcomes after the first year of UCB transplantation versus matched related donor (MRD) and matched unrelated donor (MUD) transplantation in patients with hematologic malignancies over a 20-year period. In this single-center, retrospective study, we examined the outcomes of all adult patients who underwent their first allogeneic HCT through the Duke Adult Bone Marrow Transplant program from January 1, 1996, to December 31, 2015, to allow for at least 3 years of follow-up. Patients were excluded if they died or were lost to follow-up before day 365 after HCT, received an allogeneic HCT for a disease other than a hematologic malignancy, or received cells from a haploidentical or mismatched adult donor. UCB recipients experienced a better unadjusted overall survival than MRD/MUD recipients (log rank P = .03, median overall survival: UCB not reached, MRD/MUD 7.4 years). After adjusting for selected covariates, UCB recipients who survived at least 1 year after HCT had a hazard of death that was 31% lower than that of MRD/MUD recipients (hazard ratio, 0.69; 95% confidence interval, 0.47-0.99; P = .049). This trend held true in a subset analysis of subjects with acute leukemia. UCB recipients also experienced lower rates of moderate or severe chronic graft-versus-host disease (GVHD) and nonrelapse mortality, and slower time to relapse. UCB and MRD/MUD recipients experienced similar rates of grade 2-4 acute GVHD, chronic GHVD, secondary malignancy, and subsequent allogeneic HCT. UCB is already widely used as a donor source in pediatric HCT; however, adult outcomes and adoption have historically lagged behind in comparison. Recent advancements in UCB transplantation such as the implementation of lower-intensity conditioning regimens, double unit transplants, and ex vivo expansion have improved early mortality, making UCB an increasingly attractive donor source for adults; furthermore, our findings suggest that UCB may actually be a preferred donor source for mitigating late effects of HCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtct.2021.05.002DOI Listing
August 2021

Randomised, double-blind, placebo-controlled trial of Probiotics To Eliminate COVID-19 Transmission in Exposed Household Contacts (PROTECT-EHC): a clinical trial protocol.

BMJ Open 2021 05 5;11(5):e047069. Epub 2021 May 5.

Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA

Introduction: The COVID-19 pandemic has proven to be an unprecedented challenge to worldwide health, and strategies to mitigate the spread and severity of COVID-19 infection are urgently needed. Emerging evidence suggests that the composition of the gut microbiome and modification of microbial ecology via probiotics can affect susceptibility to a wide range of infections, including respiratory tract infections. In this study, we aim to evaluate the effects of the probiotic (LGG) versus placebo on COVID-19 infection status and the gut microbiome in subjects with a household contact who has tested positive for COVID-19.

Methods And Analysis: In this double-blinded, randomised, placebo-controlled trial, we will randomise 1132 subjects having a household contact who has recently (≤7 days) tested positive for COVID-19 to daily oral LGG or placebo for 28 days. We hypothesise that taking LGG as a probiotic will protect against COVID-19 infection and reduce the severity of disease in those who become infected (primary endpoint: decreased symptoms), and will be associated with beneficial changes in the composition of the gut microbiome. Stool samples and nasal swabs will be collected to evaluate the microbiome by 16S rRNA sequencing and the presence of SARS-CoV-2 by PCR, respectively. We will also conduct multivariate analysis of demographic, behavioural, temporal, and other variables that may predict development of symptoms and other outcomes.

Ethics And Dissemination: This trial is conducted under a Food and Drug Administration Investigational New Drug for LGG, has received ethics approval by the institutional review board of Duke University and enrolment has begun. We plan to disseminate the results in peer-reviewed journals and at national and international conferences.

Trial Registration Number: NCT04399252.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2020-047069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102858PMC
May 2021

Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition.

Nature 2021 02 27;590(7846):486-491. Epub 2021 Jan 27.

Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Selective targeting of aneuploid cells is an attractive strategy for cancer treatment. However, it is unclear whether aneuploidy generates any clinically relevant vulnerabilities in cancer cells. Here we mapped the aneuploidy landscapes of about 1,000 human cancer cell lines, and analysed genetic and chemical perturbation screens to identify cellular vulnerabilities associated with aneuploidy. We found that aneuploid cancer cells show increased sensitivity to genetic perturbation of core components of the spindle assembly checkpoint (SAC), which ensures the proper segregation of chromosomes during mitosis. Unexpectedly, we also found that aneuploid cancer cells were less sensitive than diploid cells to short-term exposure to multiple SAC inhibitors. Indeed, aneuploid cancer cells became increasingly sensitive to inhibition of SAC over time. Aneuploid cells exhibited aberrant spindle geometry and dynamics, and kept dividing when the SAC was inhibited, resulting in the accumulation of mitotic defects, and in unstable and less-fit karyotypes. Therefore, although aneuploid cancer cells could overcome inhibition of SAC more readily than diploid cells, their long-term proliferation was jeopardized. We identified a specific mitotic kinesin, KIF18A, whose activity was perturbed in aneuploid cancer cells. Aneuploid cancer cells were particularly vulnerable to depletion of KIF18A, and KIF18A overexpression restored their response to SAC inhibition. Our results identify a therapeutically relevant, synthetic lethal interaction between aneuploidy and the SAC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-03114-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262644PMC
February 2021

Pharmacokinetic and Pharmacodynamic Equivalence of Pegfilgrastim-cbqv and Pegfilgrastim in Healthy Subjects.

Adv Ther 2020 10 13;37(10):4291-4307. Epub 2020 Aug 13.

Coherus BioSciences, Redwood City, CA, USA.

Introduction: Pegfilgrastim-cbqv was developed as a biosimilar of pegfilgrastim, a pegylated form of recombinant human granulocyte colony-stimulating factor approved for decreasing febrile neutropenia-associated infection in patients receiving myelosuppressive drugs. This multicenter, randomized, single-blind, partial-reference-replicated, three-sequence crossover study assessed pharmacokinetic and pharmacodynamic bioequivalence of pegfilgrastim-cbqv and pegfilgrastim in healthy subjects.

Methods: One hundred twenty-two subjects were randomized to one of three treatment sequences; each included one dose of pegfilgrastim-cbqv and two doses of pegfilgrastim separated by ≥ 28 days. The primary pharmacokinetic end points were area under the curve (AUC) from 0 to infinity (AUC) and maximum concentration (C). The primary pharmacodynamic end points were maximum absolute neutrophil count (ANC) and ANC AUC from time 0 to the last measurable observation (ANC AUC). Pharmacokinetic and pharmacodynamic bioequivalences were demonstrated if the 90% CI for the geometric mean ratio (GMR) of pegfilgrastim-cbqv to pegfilgrastim was within 80-125% for the primary end points.

Results: Pharmacokinetic bioequivalence criteria were met for C (GMR 105.0; 90% CI 95.5-115.4) and AUC (GMR 97.5; 90% CI 88.6-107.2). Pharmacodynamic bioequivalence criteria were met for ANC (GMR 99.6; 90% CI 96.2-103.2) and ANC AUC (GMR 96.7; 90% CI 92.2-101.4). Adverse events occurred in 76.0%, 76.6%, and 73.1% of subjects for pegfilgrastim-cbqv, first pegfilgrastim, and second pegfilgrastim dosing periods across treatment sequences, respectively. Investigators found no drug-related serious adverse events.

Conclusion: This study established pharmacokinetic and pharmacodynamic bioequivalence of pegfilgrastim-cbqv to pegfilgrastim. The treatments displayed similar safety profiles, including immunogenicity, with no unexpected safety findings.

Clinical Trials Registration: ClinicalTrials.gov, NCT02650973, February 2016.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12325-020-01459-yDOI Listing
October 2020

A Novel Bromine-Containing Paroxetine Analogue Provides Mechanistic Clues for Binding Ambiguity at the Central Primary Binding Site of the Serotonin Transporter.

ACS Chem Neurosci 2019 09 22;10(9):3946-3952. Epub 2019 Aug 22.

Molecular Targets and Medications Discovery Branch , National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health , 333 Cassell Drive , Baltimore , Maryland 21224 , United States.

The serotonin transporter (SERT) is the primary target for the selective serotonin reuptake inhibitors (SSRIs). However, the structural basis for the extraordinarily high binding affinity of the widely prescribed SSRI, paroxetine, to human SERT (hSERT) has not yet been fully elucidated. Our previous findings unveiled a plausible ambiguity in paroxetine's binding orientations that may constitute an integral component of this SSRI's high affinity for hSERT. Herein, we investigate factors contributing to paroxetine's high affinity by modifying both the ligand and the protein. We generated a series of bromine (Br)-containing derivatives and found that the one in which the 4-F of paroxetine had been replaced with the chemically similar but more electron-rich Br atom () had the highest affinity. By comparatively characterizing the binding of paroxetine and to both wild type (WT) and a construct harboring a paroxetine-sensitive mutation in the binding cavity, we identified a mechanistic determinant responsible for the pose ambiguity of paroxetine, which can guide future drug design.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acschemneuro.9b00375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272913PMC
September 2019

Genetic and transcriptional evolution alters cancer cell line drug response.

Nature 2018 08 8;560(7718):325-330. Epub 2018 Aug 8.

Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Human cancer cell lines are the workhorse of cancer research. Although cell lines are known to evolve in culture, the extent of the resultant genetic and transcriptional heterogeneity and its functional consequences remain understudied. Here we use genomic analyses of 106 human cell lines grown in two laboratories to show extensive clonal diversity. Further comprehensive genomic characterization of 27 strains of the common breast cancer cell line MCF7 uncovered rapid genetic diversification. Similar results were obtained with multiple strains of 13 additional cell lines. Notably, genetic changes were associated with differential activation of gene expression programs and marked differences in cell morphology and proliferation. Barcoding experiments showed that cell line evolution occurs as a result of positive clonal selection that is highly sensitive to culture conditions. Analyses of single-cell-derived clones demonstrated that continuous instability quickly translates into heterogeneity of the cell line. When the 27 MCF7 strains were tested against 321 anti-cancer compounds, we uncovered considerably different drug responses: at least 75% of compounds that strongly inhibited some strains were completely inactive in others. This study documents the extent, origins and consequences of genetic variation within cell lines, and provides a framework for researchers to measure such variation in efforts to support maximally reproducible cancer research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-018-0409-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522222PMC
August 2018

Reversing the negative psychological sequelae of exclusion: inclusion is ameliorative but not protective against the aversive consequences of exclusion.

Emotion 2013 Feb 20;13(1):139-50. Epub 2012 Aug 20.

School of Psychology, University of New South Wales, Sydney, New South Wales, Australia.

Social exclusion can have devastating personal, social, and clinical consequences, but several recent studies have identified factors that can reduce its aversive impact (e.g., distraction from rumination, control over a noise). In this study, we continued to explore possible strategies for reducing the aversive experiences of being excluded. Three experiments investigated whether an experience of inclusion reduced the impact of exclusion. Specifically, participants engaged in two rounds of a computer ball toss game (Cyberball) in which they were either included or excluded. Participants were told either that they played the two games with the same two sources (Experiment 1), with a different pair of sources (Experiment 2), or with people and then computer controlled sources (Experiment 3). We measured the impact of exclusion and inclusion on the psychological states of belonging, control, self esteem, meaningful existence, hurt feelings, anger, and affect. Across all three experiments, if inclusion occurred after exclusion then it was found to have an ameliorative benefit. However, if inclusion occurred before exclusion there was no protective benefit. Finally, we compared the ratings following one versus two experiences of exclusion, with no additive impact found. Taken together, the results indicate that inclusion can reduce the impact of exclusion, but only if it occurs after exclusion. Further, inclusion is ameliorative even when it is by a different group or a computer program.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1037/a0029521DOI Listing
February 2013

Predictors of successful outcomes after external cephalic version in singleton term breech pregnancies: a nine-year historical cohort study.

Hong Kong Med J 2012 Feb;18(1):11-9

Department of Obstetrics and Gynaecology, Kwong Wah Hospital, 25 Waterloo Road, Hong Kong.

Objective: To study the success rate, predictors for success, and pregnancy outcomes after external cephalic version.

Design: Historical cohort study.

Setting: Regional hospital, Hong Kong.

Patients: All women who had singleton term breech pregnancies at term and opted for external cephalic version during 2001 and 2009. Their demographic data, clinical and ultrasound findings, procedure details, complications, and delivery outcomes were analysed.

Main Outcome Measures: Predictive factors for successful external cephalic version.

Results: A total of 209 external cephalic versions were performed during the 9-year period. The success rate was 63% (75% for multiparous and 53% for nulliparous women). There was no significant complication. On univariate analysis, predictors of successful external cephalic version were: multiparity, unengaged presenting part, higher amniotic fluid index (≥ 10 cm), thin abdominal wall, low uterine tone, and easily palpable fetal head (subjective assessment by practitioners before external cephalic version). On multivariate analysis, only multiparity, non-engagement of the fetal buttock and thin maternal abdomen were associated with successful external cephalic version. In all, 69% of those who had successful external cephalic version succeeded in the first roll (P<0.001), and 82% of the women with successful external cephalic versions had vaginal deliveries (93% in multiparous and 69% in nulliparous women). Uptake rate of external cephalic version was studied in the latter part of the study period (2006-2009). Whilst 735 women were eligible for external cephalic version, 131 women chose to have the procedure resulting in an uptake rate of 18%.

Conclusion: External cephalic version was effective in reducing breech presentations at term and corresponding caesarean section rates, but the uptake rate was low. Further work should address the barriers to the low acceptance of external cephalic version. The results of this study could encourage women to opt for external cephalic version.
View Article and Find Full Text PDF

Download full-text PDF

Source
February 2012

Ca(v)1.2 calcium channel is glutathionylated during oxidative stress in guinea pig and ischemic human heart.

Free Radic Biol Med 2011 Oct 19;51(8):1501-11. Epub 2011 Jul 19.

School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, Crawley, WA 6009, Australia.

Glutathionylation as a posttranslational modification of proteins is becoming increasingly recognized, but its role in many diseases has not been demonstrated. Oxidative stress and alterations in calcium homeostasis are associated with the development of cardiac hypertrophy. Because the cardiac L-type Ca(2+) channel can be persistently activated after exposure to H(2)O(2), the aim of this study was to determine whether alterations in channel function were associated with glutathionylation of the α(1C) subunit (Ca(v)1.2) channel protein. Immunoblot analysis indicated that Ca(v)1.2 protein is significantly glutathionylated after exposure to H(2)O(2) and glutathione in vitro and after ischemia-reperfusion injury. L-type Ca(2+) channel macroscopic current and intracellular calcium were significantly increased in myocytes after exposure to oxidized glutathione and reversed by glutaredoxin. The increase in current correlated with an increase in open probability of the channel assessed as changes in single-channel activity after exposing the human long N-terminal Ca(v)1.2 to H(2)O(2) or oxidized glutathione. We also demonstrate that the Ca(v)1.2 channel is significantly glutathionylated in ischemic human heart. We conclude that oxidative stress is associated with an increase in glutathionylation of the Ca(v)1.2 channel protein. We suggest that the associated constitutive activity contributes to the development of pathology in ischemic heart disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.freeradbiomed.2011.07.005DOI Listing
October 2011

Symptomatic and asymptomatic infections of rotavirus, norovirus, and adenovirus among hospitalized children in Xi'an, China.

J Med Virol 2011 Aug 26;83(8):1476-84. Epub 2011 May 26.

The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Rotavirus (RV), norovirus (NoV), and adenovirus (AdV) have been reported as the common viral pathogens of acute gastroenteritis in children. To determine the prevalence of RV, NoV, and AdV infections among hospitalized children with and without symptoms of acute gastroenteritis, fecal specimens, and data on clinical symptoms were collected from 201 children with diarrhea and 53 children without diarrhea admitted to the Xi'an Children's Hospital in Xi'an, China between March 2009 and May 2010. RV, NoV, and AdV were identified in 68.7% (138/201), 20.4% (41/201), and 5.0% (10/201), respectively, of children with diarrhea. These three viruses were also detected in 13.2% (7/53), 35.9% (19/53), and 9.4% (6/53), respectively, of children without diarrhea. Diarrheal children infected with RV alone showed the average severity score of 6.5, statistically significant higher than the average score of 5.3 in children with unidentifiable viruses. GII.3 and GII.4 were the only two NoV genotypes identified, and the GII.4 sequences were genetically close to GII.4 2006b cluster. These findings highlight the importance of NoV as a causative agent of pediatric diarrhea after RV based on the clinical and epidemiological characteristics of NoV infection, and particularly convey information of asymptomatic infections of enteric viruses in young children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jmv.22108DOI Listing
August 2011

Stereological and allometric studies on neurons and axo-dendritic synapses in the superior cervical ganglia of rats, capybaras and horses.

Cell Tissue Res 2010 Aug 2;341(2):223-37. Epub 2010 Jul 2.

Research Department of Inflammation, University College London Medical School, Royal Free Campus, London, UK.

The superior cervical ganglion (SCG) in mammals varies in structure according to developmental age, body size, gender, lateral asymmetry, the size and nuclear content of neurons and the complexity and synaptic coverage of their dendritic trees. In small and medium-sized mammals, neuron number and size increase from birth to adulthood and, in phylogenetic studies, vary with body size. However, recent studies on larger animals suggest that body weight does not, in general, accurately predict neuron number. We have applied design-based stereological tools at the light-microscopic level to assess the volumetric composition of ganglia and to estimate the numbers and sizes of neurons in SCGs from rats, capybaras and horses. Using transmission electron microscopy, we have obtained design-based estimates of the surface coverage of dendrites by postsynaptic apposition zones and model-based estimates of the numbers and sizes of synaptophysin-labelled axo-dendritic synaptic disks. Linear regression analysis of log-transformed data has been undertaken in order to establish the nature of the relationships between numbers and SCG volume (V(scg)). For SCGs (five per species), the allometric relationship for neuron number (N) is N=35,067xV (scg) (0.781) and that for synapses is N=20,095,000xV (scg) (1.328) , the former being a good predictor and the latter a poor predictor of synapse number. Our findings thus reveal the nature of SCG growth in terms of its main ingredients (neurons, neuropil, blood vessels) and show that larger mammals have SCG neurons exhibiting more complex arborizations and greater numbers of axo-dendritic synapses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00441-010-1002-8DOI Listing
August 2010

Sciatic nerve of diabetic rat treated with epoetin delta: effects on C-fibers and blood vessels including pericytes.

Angiology 2010 Oct 13;61(7):651-68. Epub 2010 Jun 13.

Research Department of Inflammation, University College London Medical School, Royal Free Campus, London, UK.

In diabetes mellitus (DM) reduced motor and sensory properties of peripheral nerves are linked with the dysfunction of neural vasculature. We investigated C-fibers and microvessels of sciatic nerve of normal, DM, and DM + epoetin delta-treated rats. C-fibers immunoreactive for calcitonin gene-related peptide (CGRP), tyrosine hydroxylase (TH), epoetin receptor (EpoR), and common beta receptor subunit of the interleukin 3 receptor (IL-3Rbeta) were present in all rats, whereas in DM and epoetin-treated rats C-fibers also showed neuronal (nNOS) and inducible (iNOS) nitric oxide synthases. The cross-sectional area of CGRP-positive C-fibers was decreased in DM, but it recovered after epoetin treatment. In all conditions, vascular endothelium showed scarce immunolabeling for endothelial nitric oxide synthase (eNOS); the profound immunoreactivity for eNOS, EpoR, and IL-3Rbeta was in pericytes. Some perivascular autonomic nerves were damaged and IL-3Rbeta positive. Findings are discussed in terms of declined sensory conduction velocity in DM, its improvement after epoetin treatment, and the possible vascular contribution to these phenomena.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0003319709360030DOI Listing
October 2010

The endothelium of basilar artery of diabetic rat treated with epoetin delta.

Angiology 2010 May 8;61(4):405-14. Epub 2009 Oct 8.

Research Department of Inflammation, University College London Medical School, Royal Free Campus, London, United Kingdom.

Erythropoiesis-stimulating agents (ESAs) are used to treat anemia associated with renal failure. It is now known that these agents also show a broad range of cell- and tissue-protective effects. In the current study, we explored whether an ESA, epoetin delta, affects vascular pathology linked to diabetes mellitus (DM). In a rat model of streptozotocin-induced DM, we investigated, by pre-embedding electron-immunocytochemistry, whether epoetin delta affects DM-induced structural changes in cerebrovascular endothelium of the rat basilar artery and influences the subcellular distribution of endothelial nitric oxide synthase (eNOS). Epoetin delta treatment influenced DM-induced changes to the distribution of eNOS in, and the structure of, the endothelial cell. This may indicate potential beneficial effects of epoetin delta on cerebrovascular endothelium and suggests eNOS as a possible target molecule of epoetin delta in DM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0003319709348294DOI Listing
May 2010

Low-intensity treadmill exercise-related changes in the rat stellate ganglion neurons.

J Neurosci Res 2009 May;87(6):1334-42

Laboratory of Stochastic Stereology and Chemical Anatomy, Department of Surgery, College of Veterinary Medicine, University of São Paulo, São Paulo, Brazil.

Stellate ganglion (SG) represents the main sympathetic input to the heart. This study aimed at investigating physical exercise-related changes in the quantitative aspects of SG neurons in treadmill-exercised Wistar rats. By applying state-of-the-art design-based stereology, the SG volume, total number of SG neurons, mean perikaryal volume of SG neurons, and the total volume of neurons in the whole SG have been examined. Arterial pressure and heart rate were also measured at the end of the exercise period. The present study showed that a low-intensity exercise training program caused a 12% decrease in the heart rate of trained rats. In contrast, there were no effects on systolic pressure, diastolic pressure, or mean arterial pressure. As to quantitative changes related to physical exercise, the main findings were a 21% increase in the fractional volume occupied by neurons in the SG, and an 83% increase in the mean perikaryal volume of SG neurons in treadmill-trained rats, which shows a remarkable neuron hypertrophy. It seems reasonable to infer that neuron hypertrophy may have been the result of a functional overload imposed on the SG neurons by initial posttraining sympathetic activation. From the novel stereological data we provide, further investigations are needed to shed light on the mechanistic aspect of neuron hypertrophy: what role does neuron hypertrophy play? Could neuron hypertrophy be assigned to the functional overload induced by physical exercise?
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jnr.21961DOI Listing
May 2009

Fine structural analysis of the neuronal inclusions of frontotemporal lobar degeneration with TDP-43 proteinopathy.

J Neural Transm (Vienna) 2008 Dec 31;115(12):1661-71. Epub 2008 Oct 31.

The Sussex Centre for Advanced Microscopy, University of Sussex, Falmer, Brighton, East Sussex, BN1 9QG, UK.

TAR DNA-binding protein of 43 kDa (TDP-43) is a major component of the pathological inclusions of frontotemporal lobar degeneration with TDP-43 proteinopathy, also called FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U), and motor neuron disease (MND). TDP-43 is predominantly expressed in the nucleus and regulates gene expression and splicing. In FTLD with TDP-43 proteinopathy, neuronal inclusions present variably as cytoplasmic inclusions (NCIs), dystrophic neurites (DNs), and intranuclear inclusions (NIIs), leading to a fourfold neuropathological classification correlating with genotype. There have been few fine structural studies of these inclusions. Thus, we undertook an immunoelectron microscopic study of FTLD with TDP-43 proteinopathy, including sporadic and familial cases with progranulin (GRN) mutation. TDP-43-immunoreactive inclusions comprised two components: granular and filamentous. Filament widths, expressed as mean (range) were: NCI, 9 nm (4-16 nm); DN, 10 nm (5-16 nm); NII, 18 nm (9-50 nm). Morphologically distinct inclusion components may reflect the process of TDP-43 aggregation and interaction with other proteins: determining these latter may contribute towards understanding the heterogeneous pathogenesis of FTLD with TDP-43 proteinopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00702-008-0137-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789307PMC
December 2008

The effects of FG7142 on two types of forgetting in 18-day-old rats.

Behav Neurosci 2007 Dec;121(6):1421-5

School of Psychology, University of New South Wales, Sydney, Australia.

The authors studied the role of gamma-aminobutyric acid (GABA) in 2 types of forgetting of fear in the developing rat. One type of forgetting studied was that observed after an intermediate retention interval (the "Kamin effect"); the other type studied was that observed after a longer interval (infantile amnesia). Rats were given pairings of an auditory conditioned stimulus with shock, and learned fear was assessed by freezing. Forgetting at an intermediate retention interval (1 hr) was not alleviated by the GABA-sub(A) receptor partial inverse agonist FG7142 (0, 1, 5, or 10 mg/kg), whereas forgetting at a longer retention interval (48 hr) was alleviated. These results suggest that in the developing rat, forgetting observed at different retention intervals is mediated by different physiological mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1037/0735-7044.121.6.1421DOI Listing
December 2007
-->