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1.
Sci Rep ; 9(1): 16490, 2019 11 11.
Article in English | MEDLINE | ID: mdl-31712703

ABSTRACT

Chemotherapy treatment negatively affects the nervous and immune systems and alters gastrointestinal function and microbial composition. Outside of the cancer field, alterations in commensal bacteria and immune function have been implicated in behavioral deficits; however, the extent to which intestinal changes are related to chemotherapy-associated behavioral comorbidities is not yet known. Thus, this study identified concurrent changes in behavior, central and peripheral immune activation, colon histology, and bacterial community structure in mice treated with paclitaxel chemotherapy. In paclitaxel-treated mice, increased fatigue and decreased cognitive performance occurred in parallel with reduced microglia immunoreactivity, increased circulating chemokine expression (CXCL1), as well as transient increases in pro-inflammatory cytokine/chemokine (Il-1ß, Tnfα, Il-6, and Cxcl1) gene expression in the brain. Furthermore, mice treated with paclitaxel had altered colonic bacterial community composition and increased crypt depth. Relative abundances of multiple bacterial taxa were associated with paclitaxel-induced increases in colon mass, spleen mass, and microglia activation. Although microbial community composition was not directly related to available brain or behavioral measures, structural differences in colonic tissue were strongly related to microglia activation in the dentate gyrus and the prefrontal cortex. These data indicate that the chemotherapeutic paclitaxel concurrently affects the gut microbiome, colonic tissue integrity, microglia activation, and fatigue in female mice, thus identifying a novel relationship between colonic tissue integrity and behavioral responses that is not often assessed in studies of the brain-gut-microbiota axis.


Subject(s)
Antineoplastic Agents/adverse effects , Bacteria/drug effects , Colon/drug effects , Dysbiosis/etiology , Gastrointestinal Microbiome/drug effects , Immune System/drug effects , Inflammation/etiology , Animals , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers , Brain/drug effects , Brain/metabolism , Brain/pathology , Cognitive Dysfunction/etiology , Colon/metabolism , Colon/pathology , Cytokines/blood , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Fatigue/etiology , Female , Gene Expression Regulation/drug effects , Homeostasis/drug effects , Illness Behavior , Inflammation/metabolism , Inflammation/pathology , Inflammation Mediators/blood , Inflammation Mediators/metabolism , Mice
2.
Physiol Rep ; 6(17): e13814, 2018 09.
Article in English | MEDLINE | ID: mdl-30229567

ABSTRACT

Preeclampsia (PE), a disorder of new-onset maternal hypertension and vascular dysfunction during pregnancy, is thought to be linked to placental ischemia-induced release of prohypertensive factors and reductions of vasoprotective factors in the maternal circulation. Although markers of sympathetic nervous activity are elevated in experimental models of placental ischemia-induced hypertension and women with PE compared with their normal pregnant counterparts, the importance of adrenergic receptor signaling in the development of hypertension in PE is unknown. Therefore, we tested the hypothesis that adrenergic receptor blockade attenuates the development of placental ischemia-induced hypertension in rats. Wistar Hannover rats underwent reduced uterine perfusion pressure (RUPP) or Sham surgeries on gestational day 14. By day 19, mean arterial blood pressure (MAP) was increased in RUPP over Sham rats. Groups of RUPP and Sham pregnant rats received terazosin and propranolol (3 mg/kg per day of each via subcutaneous osmotic minipump) to block α1- and ß-adrenergic receptors, respectively, beginning on gestational day 14. Adrenergic blockade significantly attenuated the development of hypertension in the RUPP rats with a slight blood pressure-lowering response in the Sham, normal pregnant rats by day 19. In conclusion, these data implicate that placental ischemia-induced hypertension involves adrenergic receptor signaling to promote increases in blood pressure during PE.


Subject(s)
Adrenergic alpha-1 Receptor Antagonists/therapeutic use , Adrenergic beta-Antagonists/therapeutic use , Prazosin/analogs & derivatives , Pre-Eclampsia/drug therapy , Propranolol/therapeutic use , Adrenergic alpha-1 Receptor Antagonists/administration & dosage , Adrenergic beta-Antagonists/administration & dosage , Animals , Blood Pressure , Female , Ischemia/complications , Placenta/blood supply , Prazosin/administration & dosage , Prazosin/therapeutic use , Pre-Eclampsia/etiology , Pregnancy , Propranolol/administration & dosage , Rats , Rats, Wistar
3.
HIV Med ; 19(6): 376-385, 2018 07.
Article in English | MEDLINE | ID: mdl-29441669

ABSTRACT

OBJECTIVES: The aim of the study was to investigate the hypothesis of accelerated cognitive ageing in HIV-positive individuals using longitudinal assessment of cognitive performance and quantitative magnetic resonance imaging (MRI). METHODS: We assessed a broad cognitive battery and quantitative MRI metrics [voxel-based morphometry (VBM) and diffusion tensor imaging (DTI)] in asymptomatic HIV-positive men who have sex with men (15 aged 20-40 years and 15 aged ≥ 50 years), and HIV-seronegative matched controls (nine aged 20-40 years and 16 aged ≥ 50 years). RESULTS: Being HIV positive was associated with greater decreases in executive function and global cognition. Additionally, using DTI, we found that the HIV-positive group had a greater increase in mean diffusivity, but we did not find group differences in volume change using VBM. With respect to the HIV status by age group interaction, this was statistically significant for change in global cognition, with older HIV-positive individuals showing greater global cognitive decline, but there were no significant interaction effects on other measures. Lastly, change in cognitive performance was correlated with change in the DTI measures, and this effect was stronger for the HIV-positive participants. CONCLUSIONS: In the present study, we found some evidence for accelerated ageing in HIV-positive individuals, with a statistically significant HIV status by age group interaction in global cognition, although this interaction could not be explained by the imaging findings. Moreover, we also found that change in cognitive performance was correlated with change in the DTI measures, and this effect was stronger for the HIV-positive participants. This will need replication in larger studies using a similarly lengthy follow-up period.


Subject(s)
Aging/pathology , Cognitive Dysfunction/physiopathology , HIV Infections/physiopathology , HIV Infections/psychology , Magnetic Resonance Imaging , Neuroimaging , Adult , Aging/immunology , Cognition , Cognitive Dysfunction/virology , Follow-Up Studies , HIV Infections/immunology , Homosexuality, Male , Humans , Longitudinal Studies , Male , Middle Aged , Neuropsychological Tests , Time Factors , Young Adult
4.
Article in English | MEDLINE | ID: mdl-28002991

ABSTRACT

This study investigated the relationship between intraindividual variability (IIV) in reaction time and prospective memory errors in older adults using data from the Zurich Longitudinal Study of Cognitive Aging (n = 336 individuals aged 66-81 years). The results indicated that increased IIV measured from independent tasks was associated with a greater proportion of prospective memory errors. These significant findings were not influenced by age and did not vary according to prospective memory cue type. Variability is thought to reflect fluctuations in attentional and executive control and these attentional processes may also impact on prospective memory through failure to detect the target cue. The findings suggest, therefore, that measures of variability may have some potential in the identification of older persons who are more vulnerable to everyday errors such as prospective memory failures.


Subject(s)
Memory, Episodic , Reaction Time , Aged , Aged, 80 and over , Female , Humans , Individuality , Logistic Models , Male , Psychological Tests
5.
Mucosal Immunol ; 9(2): 414-27, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26242599

ABSTRACT

Despite the risk of transmitting HIV-1, mothers in resource-poor areas are encouraged to breastfeed their infants because of beneficial immunologic and nutritional factors in milk. Interestingly, in the absence of antiretroviral prophylaxis, the overwhelming majority of HIV-1-exposed, breastfeeding infants are naturally protected from infection. To understand the role of HIV-1 envelope (Env)-specific antibodies in breast milk in natural protection against infant virus transmission, we produced 19 HIV-1 Env-specific monoclonal antibodies (mAbs) isolated from colostrum B cells of HIV-1-infected mothers and investigated their specificity, evolution, and anti-HIV-1 functions. Despite the previously reported genetic compartmentalization and gp120-specific bias of colostrum HIV Env-specific B cells, the colostrum Env-specific mAbs described here demonstrated a broad range of gp120 epitope specificities and functions, including inhibition of epithelial cell binding and dendritic cell-mediated virus transfer, neutralization, and antibody-dependent cellular cytotoxicity. We also identified divergent patterns of colostrum Env-specific B-cell lineage evolution with respect to crossreactivity to gastrointestinal commensal bacteria, indicating that commensal bacterial antigens play a role in shaping the local breast milk immunoglobulin G (IgG) repertoire. Maternal vaccine strategies to specifically target this breast milk B-cell population may be necessary to achieve safe breastfeeding for all HIV-1-exposed infants.


Subject(s)
Antibodies, Monoclonal/chemistry , Antibodies, Neutralizing/chemistry , B-Lymphocytes/immunology , Colostrum/immunology , HIV Antibodies/chemistry , HIV Envelope Protein gp120/antagonists & inhibitors , Immunoglobulin G/chemistry , Antibodies, Monoclonal/biosynthesis , Antibodies, Monoclonal/isolation & purification , Antibodies, Neutralizing/biosynthesis , Antibodies, Neutralizing/isolation & purification , Antibody Affinity , Antibody Specificity , B-Lymphocytes/pathology , B-Lymphocytes/virology , Breast Feeding , Colostrum/cytology , Colostrum/virology , Cross Reactions , Dendritic Cells/immunology , Dendritic Cells/pathology , Dendritic Cells/virology , Disease Resistance/immunology , Epithelial Cells/immunology , Epithelial Cells/pathology , Epithelial Cells/virology , Female , Gastrointestinal Microbiome/immunology , HIV Antibodies/biosynthesis , HIV Antibodies/isolation & purification , HIV Envelope Protein gp120/immunology , HIV Infections/immunology , HIV Infections/pathology , HIV Infections/virology , HIV-1/immunology , Humans , Immunoglobulin G/biosynthesis , Immunoglobulin G/isolation & purification , Infant , Infectious Disease Transmission, Vertical/prevention & control , Milk, Human/chemistry , Milk, Human/immunology , Milk, Human/virology , Pregnancy , Symbiosis/immunology
6.
J Endocrinol ; 227(1): 13-24, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26285907

ABSTRACT

Adipose tissue (AT) inflammation is an emerging factor contributing to cardiovascular disease. STAT4 is a transcription factor expressed in adipocytes and in immune cells and contributes to AT inflammation and insulin resistance in obesity. The objective of this study was to determine the effect of STAT4 deficiency on visceral and peri-aortic AT inflammation in a model of atherosclerosis without obesity. Stat4(-/-)Apoe(-/-) mice and Apoe(-/-) controls were kept either on chow or Western diet for 12 weeks. Visceral and peri-aortic AT were collected and analyzed for immune composition by flow cytometry and for cytokine/chemokine expression by real-time PCR. Stat4(-/-)Apoe(-/-) and Apoe(-/-) mice had similar body weight, plasma glucose, and lipids. Western diet significantly increased macrophage, CD4+, CD8+, and NK cells in peri-aortic and visceral fat in Apoe(-/-) mice. In contrast, in Stat4(-/-)Apoe(-/-) mice, a Western diet failed to increase the percentage of immune cells infiltrating the AT. Also, IL12p40, TNFa, CCL5, CXCL10, and CX3CL1 were significantly reduced in the peri-aortic fat in Stat4(-/-)Apoe(-/-) mice. Importantly, Stat4(-/-)Apoe(-/-) mice on a Western diet had significantly reduced plaque burden vs Apoe(-/-) controls. In conclusion, STAT4 deletion reduces inflammation in peri-vascular and visceral AT and this may contribute via direct or indirect effects to reduced atheroma formation.


Subject(s)
Atherosclerosis/metabolism , Intra-Abdominal Fat/metabolism , Macrophages/metabolism , Panniculitis/metabolism , STAT4 Transcription Factor/metabolism , Animals , Aorta , Apolipoproteins E/genetics , Apolipoproteins E/metabolism , Atherosclerosis/etiology , Atherosclerosis/immunology , Atherosclerosis/pathology , Cell Polarity , Cells, Cultured , Chemokines/metabolism , Cytokines/metabolism , Diet, Western/adverse effects , Female , Intra-Abdominal Fat/immunology , Intra-Abdominal Fat/pathology , Macrophages/immunology , Macrophages/pathology , Macrophages, Peritoneal/immunology , Macrophages, Peritoneal/metabolism , Macrophages, Peritoneal/pathology , Mice, Knockout , Ovary , Panniculitis/etiology , Panniculitis/immunology , Panniculitis/pathology , Random Allocation , STAT4 Transcription Factor/genetics , Specific Pathogen-Free Organisms
7.
Mucosal Immunol ; 8(2): 316-26, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25100291

ABSTRACT

A successful HIV-1 vaccine must elicit immune responses that impede mucosal virus transmission, though functional roles of protective HIV-1 Envelope (Env)-specific mucosal antibodies remain unclear. Colostrum is a rich source of readily accessible mucosal B cells that may help define the mucosal antibody response contributing to prevention of postnatal HIV-1 transmission. To examine the HIV-1 Env-specific colostrum B-cell repertoire, single B cells were isolated from 17 chronically HIV-infected, lactating women, producing 51 blood and 39 colostrum HIV-1 Env-specific B-cell antibodies. All HIV-1 Env-specific colostrum-derived antibodies were immunoglobulin (Ig)G1 isotype and had mean heavy chain complementarity-determining region 3 (CDR3) lengths and mutation frequencies similar to those isolated from blood. However, variable heavy chain (VH) gene subfamily 1(∼)69 usage was higher among colostrum than blood HIV-1 Env-reactive antibodies (49% vs. 20%, P=0.006, Fisher's exact test). Additionally, more HIV-1 Env-specific colostrum antibodies were gp120 specific than those isolated from blood (44% vs. 16%, P=0.005, Fisher's exact test). One cross-compartment HIV-1 Env-specific clonal B-cell lineage was identified. These unique characteristics of colostrum B-cell antibodies suggest selective homing of HIV-1-specific IgG1-secreting memory B cells to the mammary gland and have implications for targeting mucosal B-cell populations by vaccination.


Subject(s)
B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Colostrum/immunology , HIV Envelope Protein gp120/immunology , HIV Infections/genetics , HIV Infections/immunology , HIV-1/immunology , Lactation , Black or African American , Antibody Formation/immunology , B-Lymphocytes/cytology , CD4 Lymphocyte Count , Clonal Evolution , Colostrum/cytology , Complementarity Determining Regions/genetics , Epitopes, B-Lymphocyte/immunology , Female , HIV Antibodies/immunology , HIV Envelope Protein gp41/immunology , HIV Infections/blood , HIV Infections/transmission , HIV Infections/virology , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Variable Region/genetics , Immunologic Memory , Immunophenotyping , Infectious Disease Transmission, Vertical , Mutation Rate , Phenotype , Somatic Hypermutation, Immunoglobulin , Viral Load
8.
Bioresour Technol ; 155: 334-41, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24463408

ABSTRACT

Six species of marine and freshwater green macroalgae were cultivated in outdoor tanks and subsequently converted to biocrude through hydrothermal liquefaction (HTL) in a batch reactor. The influence of the biochemical composition of biomass on biocrude yield and composition was assessed. The freshwater macroalgae Oedogonium afforded the highest biocrude yield of all six species at 26.2%, dry weight (dw). Derbesia (19.7%dw) produced the highest biocrude yield for the marine species followed by Ulva (18.7%dw). In contrast to significantly different yields across species, the biocrudes elemental profiles were remarkably similar with higher heating values of 33-34MJkg(-1). Biocrude productivity was highest for marine Derbesia (2.4gm(-2)d(-1)) and Ulva (2.1gm(-2)d(-1)), and for freshwater Oedogonium (1.3gm(-2)d(-1)). These species were therefore identified as suitable feedstocks for scale-up and further HTL studies based on biocrude productivity, as a function of biomass productivity and the yield of biomass conversion to biocrude.


Subject(s)
Biofuels , Chlorophyta/chemistry , Hot Temperature , Biomass , Carbon/analysis , Chlorophyta/growth & development , Fresh Water , Industrial Microbiology/instrumentation , Industrial Microbiology/methods , Species Specificity
9.
Am J Med Genet A ; 164A(1): 251-8, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24352918

ABSTRACT

Rubinstein-Taybi syndrome (RTS) and Cornelia de Lange syndrome (CdLS) are genetically heterogeneous multiple anomalies syndromes, each having a distinctive facial gestalt. Two genes (CREBBP and EP300) are known to cause RTS, and five (NIPBL, SMC1A, SMC3, RAD21, and HDAC8) have been associated with CdLS. A diagnosis of RTS or CdLS is molecularly confirmed in only 65% of clinically identified cases, suggesting that additional causative genes exist for both conditions. In addition, although EP300 and CREBBP encode homologous proteins and perform similar functions, only eight EP300 positive RTS patients have been reported, suggesting that patients with EP300 mutations might be escaping clinical recognition. We report on a child with multiple congenital abnormalities and intellectual disability whose facial features and complex phenotype resemble CdLS. However, no mutations in CdLS-related genes were identified. Rather, a novel EP300 mutation was found on whole exome sequencing. Possible links between EP300 and genes causing CdLS are evident in the literature. Both EP300 and HDAC8 are involved in the regulation of TP53 transcriptional activity. In addition, p300 and other chromatin associated proteins, including NIPBL, SMCA1, and SMC3, have been found at enhancer regions in different cell types. It is therefore possible that EP300 and CdLS-related genes are involved in additional shared pathways, producing overlapping phenotypes. As whole exome sequencing becomes more widely utilized, the diverse phenotypes associated with EP300 mutations should be better understood. In the meantime, testing for EP300 mutations in those with features of CdLS may be warranted.


Subject(s)
De Lange Syndrome/diagnosis , De Lange Syndrome/genetics , E1A-Associated p300 Protein/genetics , Exome , Frameshift Mutation , Phenotype , Autopsy , Diagnosis, Differential , Facies , Fatal Outcome , Heterozygote , Humans , Infant , Male , Rubinstein-Taybi Syndrome/diagnosis , Rubinstein-Taybi Syndrome/genetics
10.
Mucosal Immunol ; 6(4): 692-703, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23299618

ABSTRACT

Prevention of HIV-1 transmission at mucosal surfaces will likely require durable pre-existing mucosal anti-HIV-1 antibodies (Abs). Defining the ontogeny, specificities and potentially protective nature of the initial mucosal virus-specific B-cell response will be critical for understanding how to induce protective Ab responses by vaccination. Genital fluids from patients within the earliest stages of acute HIV-1 infection (Fiebig I-VI) were examined for multiple anti-HIV specificities. Gp41 (but not gp120) Env immunoglobulin (Ig)A Abs were frequently elicited in both plasma and mucosal fluids within the first weeks of transmission. However, shortly after induction, these initial mucosal gp41 Env IgA Abs rapidly declined with a t(½) of ∼2.7 days. B-cell-activating factor belonging to the TNF family (BAFF) was elevated immediately preceding the appearance of gp41 Abs, likely contributing to an initial T-independent Ab response. HIV-1 transmission frequently elicits mucosal HIV-1 envelope-specific IgA responses targeted to gp41 that have a short half-life.


Subject(s)
HIV Envelope Protein gp41/immunology , HIV Infections/immunology , HIV-1/immunology , Immunoglobulin A/immunology , Antibody Specificity/immunology , B-Cell Activating Factor/metabolism , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Female , HIV Infections/metabolism , HIV Infections/transmission , Humans , Immunity, Mucosal , Immunoglobulin A/blood , Immunoglobulin G/blood , Immunoglobulin G/immunology , Lymphocyte Activation/immunology , Male , Time Factors
11.
Ann Oncol ; 22(8): 1770-6, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21285137

ABSTRACT

BACKGROUND: Surprisingly few data are published on the relevance of even commonly used biomarkers of response to aromatase inhibitors (AIs) in advanced breast cancer. Here, we aim to determine the effectiveness of AIs in that setting according to quantitative levels of estrogen receptor (ER), progesterone receptor (PgR) and Ki67 or human epithelial growth factor receptor-2 (HER-2) status. PATIENTS AND METHODS: ER, PgR, HER-2 and Ki67 protein expressions were centrally assessed in 177 archival formalin-fixed paraffin-embedded primary or locally recurrent breast tumours from women who subsequently received AI treatment of advanced disease. RESULTS: Among ER-positive patients (n = 146), higher PgR, but not ER, levels were associated with increased time to AI treatment failure (TTF). Higher Ki67 staining was associated with decreased TTF. ER-positive/HER-2-positive patients showed a non-significant trend for decreased TTF compared with ER-positive/HER-2-negative patients. PgR level, but not Ki67, remained a significant predictor of TTF in multivariate analysis of ER-positive patients. CONCLUSIONS: Higher PgR and Ki67 levels are significantly associated with increased and decreased TTF, respectively, in ER-positive patients receiving AI treatment of advanced disease. The higher proliferation seen in PgR-negative tumours does not explain the poorer clinical responsiveness of this subgroup.


Subject(s)
Aromatase Inhibitors/therapeutic use , Biomarkers, Pharmacological/metabolism , Breast Neoplasms/drug therapy , Ki-67 Antigen/metabolism , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Female , Humans , Middle Aged , Neoplasm Staging , Postmenopause , Tissue Array Analysis , Treatment Failure , Treatment Outcome
12.
Fetal Pediatr Pathol ; 29(2): 108-19, 2010 Jan.
Article in English | MEDLINE | ID: mdl-20334486

ABSTRACT

Neu-Laxova syndrome is a rare autosomal recessive disorder characterized by severe intra-uterine growth restriction, extreme microcephaly, marked edema with skin restriction, ichthyosis, craniofacial anomalies, limb deformities, and a spectrum of central nervous system malformations. Less than 70 cases have been described since the first report in 1971. To this day the etiology and genetic basis remains unknown. Consanguinity has been reported. Some authors have postulated the syndrome to be a form of neuro-ectodermal dysplasia, while others suggest that it is a malformation syndrome secondary to severe skin restriction. Although the outcome of this syndrome is lethal, a single case of longer survival (6 months) has been reported. The majority of cases are stillborn or die shortly after birth. Thus, it is clear that Neu-Laxova exhibits a spectrum of disease, with varying degrees of phenotypic expression. We are presenting three new cases of Neu-Laxova syndrome; two were stillbirths and one lived for eleven weeks. Our microscopic and post-mortem findings in these three cases display the vast spectrum of this rare syndrome.


Subject(s)
Central Nervous System/abnormalities , Craniofacial Abnormalities/diagnostic imaging , Ichthyosis/diagnostic imaging , Microcephaly/diagnostic imaging , Stillbirth/genetics , Abnormalities, Multiple/diagnostic imaging , Central Nervous System/diagnostic imaging , Consanguinity , Ectodermal Dysplasia/diagnostic imaging , Female , Humans , Nervous System Malformations/diagnostic imaging , Phenotype , Pregnancy , Rare Diseases/diagnostic imaging , Syndrome , Ultrasonography
13.
Spinal Cord ; 47(8): 582-91, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19381157

ABSTRACT

STUDY DESIGN: Review by the spinal cord outcomes partnership endeavor (SCOPE), which is a broad-based international consortium of scientists and clinical researchers representing academic institutions, industry, government agencies, not-for-profit organizations and foundations. OBJECTIVES: Assessment of current and evolving tools for evaluating human spinal cord injury (SCI) outcomes for both clinical diagnosis and clinical research studies. METHODS: a framework for the appraisal of evidence of metric properties was used to examine outcome tools or tests for accuracy, sensitivity, reliability and validity for human SCI. RESULTS: Imaging, neurological, functional, autonomic, sexual health, bladder/bowel, pain and psychosocial tools were evaluated. Several specific tools for human SCI studies have or are being developed to allow the more accurate determination for a clinically meaningful benefit (improvement in functional outcome or quality of life) being achieved as a result of a therapeutic intervention. CONCLUSION: Significant progress has been made, but further validation studies are required to identify the most appropriate tools for specific targets in a human SCI study or clinical trial.


Subject(s)
Outcome Assessment, Health Care/methods , Spinal Cord Injuries/diagnosis , Spinal Cord Injuries/therapy , Clinical Trials as Topic/methods , Clinical Trials as Topic/standards , Humans , Outcome Assessment, Health Care/standards , Treatment Outcome
14.
J Virol ; 83(8): 3556-67, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19193811

ABSTRACT

Identifying the specific genetic characteristics of successfully transmitted variants may prove central to the development of effective vaccine and microbicide interventions. Although human immunodeficiency virus transmission is associated with a population bottleneck, the extent to which different factors influence the diversity of transmitted viruses is unclear. We estimate here the number of transmitted variants in 69 heterosexual men and women with primary subtype C infections. From 1,505 env sequences obtained using a single genome amplification approach we show that 78% of infections involved single variant transmission and 22% involved multiple variant transmissions (median of 3). We found evidence for mutations selected for cytotoxic-T-lymphocyte or antibody escape and a high prevalence of recombination in individuals infected with multiple variants representing another potential escape pathway in these individuals. In a combined analysis of 171 subtype B and C transmission events, we found that infection with more than one variant does not follow a Poisson distribution, indicating that transmission of individual virions cannot be seen as independent events, each occurring with low probability. While most transmissions resulted from a single infectious unit, multiple variant transmissions represent a significant fraction of transmission events, suggesting that there may be important mechanistic differences between these groups that are not yet understood.


Subject(s)
Genetic Variation , HIV Infections/transmission , HIV Infections/virology , HIV-1/physiology , Adult , Cluster Analysis , Female , HIV-1/classification , HIV-1/genetics , Humans , Male , Molecular Sequence Data , Phylogeny , RNA, Viral/genetics , Sequence Analysis, DNA , Sequence Homology , Young Adult
17.
Cancer Chemother Pharmacol ; 53(4): 341-8, 2004 Apr.
Article in English | MEDLINE | ID: mdl-14722733

ABSTRACT

Idoxifene is a novel selective oestrogen receptor modulator (SERM) which had greater binding affinity for the oestrogen receptor (ER) and reduced agonist activity compared with tamoxifen in preclinical studies. In a randomized phase II trial in 56 postmenopausal patients with progressive locally advanced/metastatic breast cancer we assessed whether idoxifene showed evidence of activity compared with an increased 40 mg/day dose of tamoxifen in patients who had previously demonstrated resistance to the standard 20 mg/day dose of tamoxifen. Of 47 patients eligible for response (25 idoxifene, 22 tamoxifen), two partial responses and two disease stabilizations (SD) for >6 months were seen with idoxifene (overall clinical benefit rate 16%, 95% CI 4.5-36.1%). The median duration of clinical benefit was 9.8 months. In contrast, no objective responses were seen with the increased 40 mg/day dose of tamoxifen, although two patients had SD for 7 and 14 months (clinical benefit rate 9%, 95% CI 1.1-29.2%). Idoxifene was well tolerated and the reported possible drug-related toxicities were similar in frequency to those with tamoxifen (hot flushes 13% vs 15%, mild nausea 20% vs 15%). Endocrine and lipid analysis in both groups showed a similar significant fall in serum follicle-stimulating hormone and luteinizing hormone after 4 weeks, together with a significant rise in sex hormone binding globulin levels and 11% reduction in serum cholesterol levels. In conclusion, while idoxifene was associated with only modest evidence of clinical activity in patients with tamoxifen-resistant breast cancer, its toxicity profile and effects on endocrine/lipid parameters were similar to those of tamoxifen.


Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/drug therapy , Tamoxifen/analogs & derivatives , Tamoxifen/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Hormonal/adverse effects , Antineoplastic Agents, Hormonal/pharmacokinetics , Biological Availability , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Double-Blind Method , Drug Resistance, Neoplasm , Female , Humans , Middle Aged , Neoplasm Invasiveness , Neoplasm Metastasis , Receptors, Cell Surface/metabolism , Receptors, Estrogen/metabolism , Tamoxifen/adverse effects , Tamoxifen/pharmacokinetics , Treatment Outcome , United Kingdom
18.
J Steroid Biochem Mol Biol ; 87(1): 35-45, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14630089

ABSTRACT

Recent clinical trials indicate that the third-generation aromatase inhibitors may be more effective than tamoxifen as first line endocrine therapy in ER+ metastatic breast cancer in postmenopausal women. This review will focus exclusively on the pharmacology of the non-steroidal inhibitor letrozole. Aromatase derived from a variety of sources is inhibited at low nM concentrations of the drug. In non-cellular systems, letrozole is 2-5 times more potent than anastrozole and exemestane in its inhibition of aromatase, whilst in cellular systems it is 10-20 times more potent. Anti-tumour effects of letrozole have been demonstrated in several animal models. In postmenopausal women, letrozole commonly suppresses circulating concentrations of estrone and estradiol to below the sensitivity limit of the assays used to measure them. In a recent randomized cross-over study, letrozole (2.5mg daily) achieved a significantly greater suppression of the plasma concentrations of both estrone and estrone sulphate than anastrozole (1mg daily) and a greater inhibition of in vivo aromatization. Letrozole appears to have a small effect on adrenal steroidogenesis such that a small number of patients exhibit an abnormal response to synthetic ACTH during letrozole therapy. This is unlikely to have any clinical significance. In short-term studies letrozole has been shown to increase markers of bone resorption indicating the need to monitor bone integrity when the drug is used for extended periods of time. A consistent effect of letrozole on serum lipids has not been demonstrated.


Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Nitriles/pharmacology , Triazoles/pharmacology , Adrenocorticotropic Hormone/blood , Animals , Antineoplastic Agents/adverse effects , Antineoplastic Agents/metabolism , Aromatase/metabolism , Aromatase Inhibitors , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/secondary , Clinical Trials as Topic , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Estradiol/blood , Estrone/analogs & derivatives , Estrone/blood , Humans , Letrozole , Nitriles/adverse effects , Nitriles/chemistry , Nitriles/metabolism , Triazoles/adverse effects , Triazoles/chemistry , Triazoles/metabolism
19.
J Steroid Biochem Mol Biol ; 86(3-5): 255-63, 2003 Sep.
Article in English | MEDLINE | ID: mdl-14623519

ABSTRACT

Third generation aromatase inhibitors have excellent specificity. Some reports indicate that letrozole may have a minor effect on cortisol synthesis but these were not confirmed: valid comparisons with other aromatase inhibitors requires randomised study. The putative use of a third generation inhibitor as a single agent in premenopausal women has been investigated using YM511. It was hypothesised that in this situation site-specific suppression of estrogens in breast carcinomas, without systemic effects, may lead to a down-regulation of tumour proliferation. Plasma levels of androstenedione and testosterone were significantly increased by 2 weeks treatment with YM511. Mean plasma estrone levels were suppressed, but some plasma estradiol levels were abnormally high and others abnormally low. These differential effects of YM511 on circulating estrogens supported the concept that peripheral synthesis of estrogens might be suppressed while ovarian production remained high. However, YM511 did not demonstrate anti-proliferative effects in hormone sensitive breast carcinomas. Consideration of the pharmacology of the estrogen receptor during tamoxifen therapy indicates that tamoxifen effectively saturates the receptor (>99.94% occupancy) in postmenopausal women. The addition of an aromatase inhibitor in this situation would be very unlikely to affect the biological activity of the estrogen receptor. This provides a possible explanation why the clinical efficacy of tamoxifen combined with an aromatase inhibitor appears to be equivalent to that of tamoxifen alone.


Subject(s)
Aromatase Inhibitors , Enzyme Inhibitors/pharmacology , Premenopause/drug effects , Tamoxifen/pharmacology , Adrenocorticotropic Hormone/pharmacology , Animals , Breast Neoplasms/drug therapy , Clinical Trials as Topic , Drug Interactions , Enzyme Inhibitors/metabolism , Estrogen Antagonists/pharmacology , Estrogens/blood , Female , Humans , Menstrual Cycle/blood , Menstrual Cycle/drug effects , Premenopause/blood , Receptors, Estrogen/drug effects , Receptors, Estrogen/metabolism , Tamoxifen/analogs & derivatives , Tamoxifen/metabolism
20.
Obstet Gynecol ; 100(2): 305-10, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12151154

ABSTRACT

OBJECTIVE: To determine the feasibility of using calculated nucleated red blood cell (RBC) counts from histologic placental slides to predict newborn nucleated RBC counts. METHODS: This retrospective study compared absolute nucleated RBC counts from 24 newborns, diagnosed with fetal distress in labor, with counts calculated from their histologic placental slides. A simple linear regression model was tested with newborn nucleated RBC counts as the dependent variable and calculated placental nucleated RBC counts as the independent variable. RESULTS: The mean +/- standard deviation newborn nucleated RBC count was 4.81 x 10(9) +/- 5.46 x 10(9)/L compared with 1.37 x 10(9) +/- 1.78 x 10(9)/L calculated from placental sections. These data were normalized by logarithmic transformation. A significant linear regression was obtained, r(2) = 0.74, P <.001. The prediction equation obtained was natural logarithm (newborn nucleated RBC count) is equal to 1.002 x natural logarithm (placental nucleated RBC count) + 1.173. CONCLUSION: It is feasible to calculate nucleated RBC counts from histologic slides of the placenta that are predictive of newborn nucleated RBC counts. Further work on more homogeneous groups of subjects is necessary to increase the precision of the method. The placenta could serve as a surrogate source for newborn whole blood nucleated RBC counts around the time of birth.


Subject(s)
Erythroblasts/cytology , Fetal Distress/blood , Infant, Newborn/blood , Placenta/cytology , Erythrocyte Count , Feasibility Studies , Female , Gestational Age , Humans , Linear Models , Predictive Value of Tests , Pregnancy , Probability , Reference Values , Registries , Retrospective Studies , Sensitivity and Specificity
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