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1.
Parasite Immunol ; 39(10)2017 Oct.
Article in English | MEDLINE | ID: mdl-28748530

ABSTRACT

Humoral immunity develops in the spleen during blood-stage Plasmodium infection. This elicits parasite-specific IgM and IgG, which control parasites and protect against malaria. Studies in mice have elucidated cells and molecules driving humoral immunity to Plasmodium, including CD4+ T cells, B cells, interleukin (IL)-21 and ICOS. IL-6, a cytokine readily detected in Plasmodium-infected mice and humans, is recognized in other systems as a driver of humoral immunity. Here, we examined the effect of infection-induced IL-6 on humoral immunity to Plasmodium. Using P. chabaudi chabaudi AS (PcAS) infection of wild-type and IL-6-/- mice, we found that IL-6 helped to control parasites during primary infection. IL-6 promoted early production of parasite-specific IgM but not IgG. Notably, splenic CD138+ plasmablast development was more dependent on IL-6 than germinal centre (GC) B-cell differentiation. IL-6 also promoted ICOS expression by CD4+ T cells, as well as their localization close to splenic B cells, but was not required for early Tfh-cell development. Finally, IL-6 promoted parasite control, IgM and IgG production, GC B-cell development and ICOS expression by Tfh cells in a second model, Py17XNL infection. IL-6 promotes CD4+ T-cell activation and B-cell responses during blood-stage Plasmodium infection, which encourages parasite-specific antibody production.


Subject(s)
B-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/immunology , Interleukin-6/immunology , Lymphocyte Activation/immunology , Malaria/immunology , Plasmodium chabaudi/immunology , Animals , Antibodies, Protozoan/immunology , Cytokines/metabolism , Female , Immunity, Humoral/immunology , Immunoglobulin G/immunology , Immunoglobulin M/immunology , Inducible T-Cell Co-Stimulator Protein/metabolism , Interleukin-6/genetics , Interleukins/immunology , Malaria/parasitology , Mice , Mice, Inbred C57BL , Mice, Knockout , Spleen/immunology , Syndecan-1/metabolism
2.
Curr Oncol ; 24(6): e494-e502, 2017 Dec.
Article in English | MEDLINE | ID: mdl-29270058

ABSTRACT

BACKGROUND: As cure rates for breast cancer improve, there is increasing evidence that late effects of treatment-and impaired fertility in particular-are emerging as important concerns among young breast cancer survivors. Older reports have evaluated the occurrence of amenorrhea after treatment, but few data have been reported about the incidence of biochemical evidence for impaired ovarian function in patients who do not become overtly menopausal. METHODS: We conducted a cross-sectional study evaluating anti-Müllerian hormone (amh) in premenopausal chemotherapy-treated breast cancer survivors and control patients. Random serum levels of amh and other relevant clinical data were collected for 100 premenopausal chemotherapy-treated breast cancer survivors and 76 control subjects. Subgroup analyses were performed for women with regular menstrual cycles at the time of amh testing. RESULTS: After adjustment for age, amh was significantly lower in the overall group of patients receiving chemotherapy (p = 0.002) and in the subgroup reporting normal cycles (p = 0.03). Cyclophosphamide produced a significant dose-dependent reduction in amh (p < 0.001); trastuzumab was associated with increased amh in survivors with normal cycles. Overall, serum amh in survivors was roughly equivalent to that measured in control patients 12 years older. CONCLUSIONS: Young breast cancer survivors often experience significant impairment of ovarian function despite having normal menstrual cycles after treatment. Those results have important implications for patient counselling and the timing of possible referral to a fertility specialist.

3.
Immunol Cell Biol ; 93(2): 198-212, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25385067

ABSTRACT

Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that has an important role at mucosal sites in a wide range of immune responses including infection, allergy and auto-immunity. γδ T cells are recognized as IL-17 producers, but based on the level of CD3 expression, we now define the remarkable ability of a CD3(bright) γδ T-cell subset with an effector memory phenotype to rapidly produce IL-17A, but not interferon-γ. CD3(bright) γδ T cells uniformly express the canonical germline encoded Vγ6/Vδ1(+) T-cell receptor. They are widely distributed with a preferential representation in the lungs and skin are negatively impacted in the absence of retinoic acid receptor-related orphan receptor gammat expression or endogenous flora. This population responded rapidly to various stimuli in a mechanism involving IL-23 and NOD-like receptor family, pyrin domain containing 3 (NLRP3)-inflammasome-dependent IL-1ß. Finally, we demonstrated that IL-17-producing CD3(bright) γδ T cells responded promptly and strongly to pneumococcal infection and during skin inflammation. Here, we propose a new way to specifically analyze IL-17-producing Vγ6/Vδ1(+) T cells based on the level of CD3 signals. Using this gating strategy, our data reinforce the crucial role of this γδ T-cell subset in respiratory and skin disorders.


Subject(s)
CD3 Complex/metabolism , Interleukin-17/biosynthesis , Receptors, Antigen, T-Cell, gamma-delta/metabolism , T-Lymphocytes/immunology , Amino Acid Sequence , Aminoquinolines/pharmacology , Animals , CD3 Complex/chemistry , Carrier Proteins/metabolism , Germ Cells/drug effects , Homeostasis/drug effects , Imiquimod , Immunity , Inflammasomes/drug effects , Inflammasomes/metabolism , Interleukin-1beta/metabolism , Interleukin-23 , Lung/drug effects , Lung/immunology , Lymphocyte Subsets/drug effects , Lymphocyte Subsets/immunology , Male , Mice, Inbred C57BL , Molecular Sequence Data , NLR Family, Pyrin Domain-Containing 3 Protein , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Phenotype , Skin/drug effects , Skin/immunology , T-Lymphocytes/drug effects
4.
Epidemiol Infect ; 143(7): 1477-85, 2015 May.
Article in English | MEDLINE | ID: mdl-25195643

ABSTRACT

There exists an urgent need to develop iterative risk assessment strategies of zoonotic diseases. The aim of this study is to develop a method of prioritizing 98 zoonoses derived from animal pathogens in Japan and to involve four major groups of stakeholders: researchers, physicians, public health officials, and citizens. We used a combination of risk profiling and analytic hierarchy process (AHP). Profiling risk was accomplished with semi-quantitative analysis of existing public health data. AHP data collection was performed by administering questionnaires to the four stakeholder groups. Results showed that researchers and public health officials focused on case fatality as the chief important factor, while physicians and citizens placed more weight on diagnosis and prevention, respectively. Most of the six top-ranked diseases were similar among all stakeholders. Transmissible spongiform encephalopathy, severe acute respiratory syndrome, and Ebola fever were ranked first, second, and third, respectively.


Subject(s)
Data Interpretation, Statistical , Health Priorities , Zoonoses/prevention & control , Animals , Female , Hemorrhagic Fever, Ebola/prevention & control , Humans , Incidence , Japan , Male , Prion Diseases/prevention & control , Public Health , Risk Assessment , Severe Acute Respiratory Syndrome/prevention & control , Surveys and Questionnaires
5.
Prenat Diagn ; 35(9): 859-63, 2015 Sep.
Article in English | MEDLINE | ID: mdl-25989740

ABSTRACT

OBJECTIVES: Prenatal diagnosis of critical congenital heart disease, which requires surgical or catheter intervention in the first 30 days of life, allows for delivery at a specialized center and can reduce preoperative morbidity and mortality. We sought to identify the risk factors for a missed prenatal diagnosis of critical congenital heart disease. METHODS: Patients presenting to the Children's Hospital of Wisconsin with critical congenital heart disease from 2007 to 2013 were included. Those with a prenatal diagnosis were compared with those with a postnatal diagnosis. RESULTS: The cohort included 535 patients with prenatal diagnosis made in 326 (61%). The prenatal diagnostic rate improved from 44% in 2007 to 69% in 2013. Independent factors associated with a postnatal diagnosis were a lesion that required a view other than a four chamber view to make the diagnosis (p < 0.0001), absence of another organ system anomaly (p < 0.0001), and living in a higher poverty (p = 0.02) or lower population density communities (p = 0.002). CONCLUSIONS: While the prenatal diagnostic rate for critical congenital heart disease is improving, those living in impoverished or rural communities are at highest risk of not having a diagnosis made prenatally. Interventions to improve prenatal detection of congenital heart disease should target these vulnerable areas.


Subject(s)
Delayed Diagnosis/statistics & numerical data , Healthcare Disparities/statistics & numerical data , Heart Defects, Congenital/diagnostic imaging , Ultrasonography, Prenatal , Female , Heart Defects, Congenital/therapy , Humans , Infant, Newborn , Male , Multivariate Analysis , Pregnancy , Retrospective Studies , Risk Factors , Socioeconomic Factors , Wisconsin
6.
Eur J Vasc Endovasc Surg ; 48(2): 147-52, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24882423

ABSTRACT

OBJECTIVES: Despite a decreasing incidence of abdominal aortic aneurysm (AAA), the cost-effectiveness of AAA ultrasound screening can be improved by reducing the screening costs and increasing the uptake rates. The BVI 9600 (BVI) is a promising tool for this purpose as it is inexpensive and can detect AAA without a trained operator. This study aims to investigate whether the BVI can be used to detect AAA for the purpose of a low-cost outreach screening approach. METHODS: A total of 142 subjects had their abdominal aortae measured by five sonographers using the BVI and a conventional ultrasound machine. The examination included four anterior-posterior measurements at four equally spaced scanning locations from the xiphisternum to the umbilicus. The measurements produced by each machine were compared using Bland-Altman plots, followed by an analysis of the AAA detection performance. RESULTS: The BVI measured the aortic diameter to within 0.88-1.56 cm of the true diameter, exceeding the 0.5 cm "clinically acceptable difference" (CAD). Its accuracy was poorer when measuring the aneurysmal aortae (mean difference -0.56 cm, variability 1.72 cm) than normal aortae (mean difference 0.02 cm, variability 0.76 cm). Nine out of 52 aneurysms were not detected due to undersizing measurement and non-visualization of the aortae. CONCLUSIONS: At present, the BVI is not sufficiently accurate to detect AAA for screening purposes. A number of technical features require improvement.


Subject(s)
Aorta, Abdominal/diagnostic imaging , Aortic Aneurysm, Abdominal/diagnostic imaging , Dilatation, Pathologic , Equipment Design , Humans , Observer Variation , Predictive Value of Tests , Reproducibility of Results , Ultrasonography
7.
Epidemiol Infect ; 142(9): 2000-12, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24284038

ABSTRACT

Neisseria meningitidis is the main cause of bacterial meningitis and sepsis in the UK, and can potentially be lethal or cause long-term sequelae. Bexsero® (4CMenB) is a new multi-component vaccine approved by the European Commission for use in individuals aged ⩾2 months. A theoretical transmission model was constructed to assess the long-term effectiveness of Bexsero compared to standard care. The model was populated with UK-specific demographic data and calibrated to ensure that the transmission dynamics of meningococcal disease in the UK were adequately simulated. The model showed the best strategy to be a routine vaccination programme at ages 2, 3, 4, 12 months and 14 years combined with a 5-year catch-up programme in toddlers aged 12-24 months and adolescents aged 15-18 years. This would lead to a 94% reduction in meningococcal cases or 150 000 cases and 15 000 deaths over a 100-year time-frame.


Subject(s)
Meningococcal Infections/prevention & control , Meningococcal Vaccines/immunology , Adolescent , Adult , Aged , Child , Child, Preschool , Humans , Infant , Meningococcal Infections/epidemiology , Middle Aged , Models, Biological , Neisseria meningitidis/classification , Neisseria meningitidis/immunology , Uncertainty , United Kingdom/epidemiology , Young Adult
8.
Bioprocess Biosyst Eng ; 37(2): 193-203, 2014 Feb.
Article in English | MEDLINE | ID: mdl-23754323

ABSTRACT

Oxygen mass transfer was studied in conventional, bead mill and baffled roller bioreactors. Using central composite rotational design, impacts of size, rotation speed and working volume on the oxygen mass transfer were evaluated. Baffled roller bioreactor outperformed its conventional and bead mill counterparts, with the highest k(L)a obtained in these configurations being 0.58, 0.19, 0.41 min(-1), respectively. Performances of the bead mill and baffled roller bioreactor were only comparable when a high bead loading (40%) was applied. Regardless of configuration increase in rotation speed and decrease in working volume improved the oxygen mass transfer rate. Increase in size led to enhanced mass transfer and higher k(L)a in baffled roller bioreactor (0.49 min(-1) for 2.2 L and 1.31 min(-1) for 55 L bioreactors). Finally, the experimentally determined k(L)a in the baffled roller bioreactors of different sizes fit reasonably well to an empirical correlation describing the k(L)a in terms of dimensionless numbers.


Subject(s)
Bioreactors , Oxygen/metabolism , Air
9.
Osteoporos Int ; 24(1): 197-207, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22358317

ABSTRACT

UNLABELLED: Widespread poor vitamin D status, a health risk for bone disease, increases the need for new food sources of vitamin D. Light-exposed edible mushrooms synthesize vitamin D(2). Bioavailability, safety, and efficacy of high levels of vitamin D(2) from mushrooms to support bone health was established in chronically fed growing rats. INTRODUCTION: Poor vitamin D status from reduced sun exposure is made worse by limited access to vitamin D-containing foods. Exposing white button mushrooms to ultraviolet B (UVB) light markedly increases their vitamin D(2) content, creating a new food source of vitamin D. We used a growing rat model to determine safety, bioavailability, and efficacy in support of bone growth by vitamin D(2) from UVB-exposed mushrooms. METHODS: We fed 150 weanling female rats one of five diets for 10 weeks, all formulated on AIN-93 G. Control diets contained no mushrooms either with or without vitamin D(3). Other diets contained 2.5% and 5.0% of UVB-exposed or -unexposed mushrooms. Safety of the high levels of vitamin D(2) from mushrooms was assessed by animal growth and by Von Kossa staining for soft tissue calcification. Bioavailability was determined from changes in circulating levels of 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH). Efficacy in support of bone growth was determined from measures of femur bending properties, size, mineralization, and microarchitecture. RESULTS: Diets containing 2.5% and 5.0% light-exposed mushrooms significantly raised 25(OH)D and suppressed PTH levels compared to control-fed rats or rats fed 5.0% mushroom unexposed to light. Microarchitecture and trabecular mineralization were only modestly higher in the light-treated mushroom-fed rats compared to the controls. Von Kossa staining revealed no soft tissue calcification despite very high plasma 25(OH)D. CONCLUSIONS: Vitamin D(2) from UVB-exposed mushrooms is bioavailable, safe, and functional in supporting bone growth and mineralization in a growing rat model without evidence of toxicity.


Subject(s)
Agaricales/radiation effects , Animal Nutritional Physiological Phenomena/physiology , Bone Development/drug effects , Ergocalciferols/pharmacology , Ultraviolet Rays , Agaricales/chemistry , Animals , Biomarkers/blood , Bone Development/physiology , Diet , Ergocalciferols/adverse effects , Ergocalciferols/pharmacokinetics , Female , Femur/diagnostic imaging , Femur/physiology , Growth/drug effects , Nutritive Value/physiology , Rats , Rats, Sprague-Dawley , X-Ray Microtomography
10.
Radiography (Lond) ; 29 Suppl 1: S81-S86, 2023 05.
Article in English | MEDLINE | ID: mdl-36828748

ABSTRACT

INTRODUCTION: The healthcare support needs of the lesbian, gay, bisexual (LGB) and transgender community are becoming an emerging area of healthcare research. Providing person-centred care is World Health Organisation policy and as such it is important that Radiography services can demonstrate areas in which they are working with people to design, develop and feedback on the services that they receive. This research aimed to establish how cancer treatment impacted on the identities of LGB people, their experiences of care, and their engagement with developing a practitioner guide. METHODS: This cooperative inquiry is underpinned by person-centred philosophy and participatory research principles. Participants were nine lesbian, gay, and bisexual people affected by cancer. Each engaged in two facilitated, audio-recorded conversations to explore their experiences of cancer care. An analytical framework based on Mezirow's Transformational Theory was used to organise the data, followed by detailed content analysis to develop themes. RESULTS: Participants included men and women, aged 45-68, who had experienced different cancers. They explored how cancer treatment had impacted on them, and worked with the researcher and stakeholders to establish a seven-recommendation practitioner guide aimed at improving LGB people's care experiences. Their accounts revealed a broad range of issues that both corroborate and build on existing evidence. Themes highlighted expectations and experiences of both assumptions and prejudice in healthcare interactions. These experiences, along with misinterpretation of relationships with significant others, led to feelings of discomfort and reserve about self-expression. Findings of the research are presented in the following key areas: Dilemmas of attending oncology appointments; Inclusive experiences of care; and Formulation of the practitioner guide. CONCLUSION: The research findings enabled development of a national practitioner guide with the participants and key stakeholders to raise awareness of the needs of LGB persons affected by cancer and support better care. IMPLICATIONS FOR PRACTICE: By providing real-life accounts this research adds to understanding of how LGB persons interact with services, developing evidence to support cultural competence within the profession of Radiography and oncology services more broadly.


Subject(s)
Homosexuality, Female , Neoplasms , Sexual and Gender Minorities , Male , Humans , Female , Bisexuality , Delivery of Health Care , Neoplasms/therapy
11.
Lupus ; 21(13): 1459-62, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22952321

ABSTRACT

Collapsing glomerulopathy (CG), characterized by collapse of the glomerular capillary loops onto the mesangial stalks is rarely associated to systemic lupus erythematosus (SLE). Recently a genetic predisposition to HIV associated nephropathy (HIVAN) has been shown in Afro-Americans: MYH9 polymorhism in 2008 and then APOL1 variants (G1 and G2 alleles) in 2010 were shown to be strongly associated with HIVAN. We describe here for the first time the association of CG in a young Afro-American female with SLE having a homozygous mutation of APOL1. The clinical history, laboratory findings and immunofluorescence all confirmed a diagnosis of SLE. However, studies for factors associated with collapsing glomerulopathy in other situations were consistently negative. As this Afro-American patient developed a CG, we performed genotyping of APOL1. It was found that she is homozygotic for the G2 allele of APOL1. Despite.


Subject(s)
Apolipoproteins/genetics , Black or African American/genetics , Homozygote , Kidney Glomerulus/pathology , Lipoproteins, HDL/genetics , Lupus Erythematosus, Systemic/genetics , Lupus Nephritis/genetics , Mutation , Apolipoprotein L1 , Biopsy , Female , Fluorescent Antibody Technique , Genetic Predisposition to Disease , Humans , Immunosuppressive Agents/therapeutic use , Lupus Erythematosus, Systemic/ethnology , Lupus Erythematosus, Systemic/pathology , Lupus Erythematosus, Systemic/therapy , Lupus Nephritis/ethnology , Lupus Nephritis/pathology , Lupus Nephritis/therapy , Phenotype , Plasma Exchange , Predictive Value of Tests , Renal Dialysis , Risk Factors , Treatment Outcome , Young Adult
12.
Nat Commun ; 13(1): 2989, 2022 May 30.
Article in English | MEDLINE | ID: mdl-35637190

ABSTRACT

Erebus volcano, Antarctica, with its persistent phonolite lava lake, is a classic example of an evolved, CO2-rich rift volcano. Seismic studies provide limited images of the magmatic system. Here we show using magnetotelluric data that a steep, melt-related conduit of low electrical resistivity originating in the upper mantle undergoes pronounced lateral re-orientation in the deep crust before reaching shallower magmatic storage and the summit lava lake. The lateral turn represents a structural fault-valve controlling episodic flow of magma and CO2 vapour, which replenish and heat the high level phonolite differentiation zone. This magmatic valve lies within an inferred, east-west structural trend forming part of an accommodation zone across the southern termination of the Terror Rift, providing a dilatant magma pathway. Unlike H2O-rich subduction arc volcanoes, CO2-dominated Erebus geophysically shows continuous magmatic structure to shallow crustal depths of < 1 km, as the melt does not experience decompression-related volatile supersaturation and viscous stalling.

13.
Am J Transplant ; 11(1): 56-65, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21199348

ABSTRACT

The significance of C4d-Banff scores in protocol biopsies of kidney transplant recipients with preformed donor-specific antibodies (DSA) has not been determined. We reviewed 157 protocol biopsies from 80 DSA+ patients obtained at 3 months and 1 year post-transplant. The C4d Banff scores (1,2,3) were associated with significant increments of microcirculation inflammation (MI) at both 3 months and 1 year post-transplant, worse transplant glomerulopathy and higher class II DSA-MFI (p < 0.01). Minimal-C4d had injury intermediate between negative and focal, while focal and diffuse-C4d had the same degree of microvascular injury. A total of 54% of patients had variation of C4d score between 3 months and 1 year post-transplant. Cumulative (3 month + 1 year) C4d scores correlated with long-term renal function worsening (p = 0.006). However, C4d staining was not a sensitive indicator of parenchymal disease, 55% of C4d-negative biopsies having evidence of concomitant MI. Multivariate analysis demonstrated that the presence of MI and class II DSA at 3 months were associated with a fourfold increased risk of progression to chronic antibody-mediated rejection independently of C4d (p < 0.05). In conclusion, the substantial fluctuation of C4d status in the first year post-transplant reflects a dynamic humoral process. However, C4d may not be a sufficiently sensitive indicator of activity, MI and DSA being more robust predictors of bad outcome.


Subject(s)
Complement C4b/immunology , Graft Rejection/immunology , Kidney Transplantation/immunology , Peptide Fragments/immunology , Adult , Aged , Antibodies , Biopsy , Graft Survival/immunology , Humans , Kidney/immunology , Kidney Transplantation/pathology , Microcirculation/immunology , Middle Aged
14.
Am J Transplant ; 11(7): 1478-87, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21668629

ABSTRACT

In heart transplants, the significance of very late rejection (after 7 years post-transplant, VLR) detected by routine endomyocardial biopsies (EMB) remains uncertain. Here, we assessed the prevalence, histopathological and immunological phenotype, and outcome of VLR in clinically stable patients. Between 1985 and 2009, 10 662 protocol EMB were performed at our institution in 398 consecutive heart transplants recipients. Among the 196 patients with >7-year follow-up, 20 (10.2%) presented subclinical ≥3A/2R-ISHLT rejection. The VLR group was compared to a matched control group of patients without rejection. All biopsies were stained for C4d/C3d/CD68 with sera screened for the presence of donor-specific antibodies (DSAs). In addition to cellular infiltrates with myocyte damage, 60% of VLR patients had evidence of intravascular macrophages. C4d and/or C3d-capillary deposition was found in 55% VLR EMB. All cases of VLR associated with microcirculation injury had DSAs (mean DSA(max) -MFI = 1751 ± 583). This entity was absent from the control group (p < 0.0001). Finally, after a similar follow-up postreference EMB of 6.4 ± 1 years, the mean of CAV grade was 0.76 ± 0.18 in the control group compared to 2.06 ± 0.26 in the VLR group respectively, p = 0.001). There was no difference in patient survival between study and control groups. In conclusion, VLR is frequently associated with complement-cascade activation, microvascular injury and DSA, suggesting an antibody-mediated process. VLR is associated with a dramatic progression to severe CAV in long-term follow-up.


Subject(s)
Graft Rejection/immunology , Graft Rejection/pathology , Heart Transplantation/pathology , Adult , Antibodies/immunology , Complement Activation , Female , Follow-Up Studies , Heart Transplantation/immunology , Heart Transplantation/mortality , Humans , Male , Middle Aged , Retrospective Studies , Tissue Donors
15.
J Phys Chem A ; 115(18): 4804-10, 2011 May 12.
Article in English | MEDLINE | ID: mdl-21500846

ABSTRACT

Electron affinities, ionization potentials, and redox potentials for DNA bases, base pairs, and N-methylated derivatives are computed at the DFT/M06-2X/6-31++G(d,p) level of theory. Redox properties of a guanine-guanine stack model are explored as well. Reduction and oxidation potentials are in good agreement with the experimental ones. Electron affinities of base pairs were found to be negative. Methylation of canonical bases affects the ionization potentials the most. Base pair formation and base stacking lower ionization potentials by 0.3 eV. Pairing of guanine with the 5-methylcytosine does not seem to influence the redox properties of this base pair much.


Subject(s)
Base Pairing , DNA/chemistry , Electrons , Quantum Theory , Hydrogen Bonding , Models, Molecular , Oxidation-Reduction
16.
Child Care Health Dev ; 37(5): 671-8, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21166834

ABSTRACT

BACKGROUND: Increasing numbers of children are at-risk for behavioural and emotional disorders, a phenomenon contributing to increased use of pharmacological interventions for paediatric clients. Adverse side effects and other risks associated with pharmacological approaches have helped fuel interest in nutritional interventions for behaviourally at-risk children. METHODS: The current randomized clinical trial evaluates the efficacy of a neurochemical intervention involving the glutamine and glutamate analogue L-theanine and 5-hydroxytryptophan, the precursor for serotonin, with children adopted from traumatic backgrounds. RESULTS: Results include significant increases in urinary levels of the biomarkers for serotonin and gamma-aminobutyric acid, coupled with significant decreases in parent reports of the children's behaviour problems. CONCLUSIONS: While further research is needed, these initial findings are encouraging and are consistent with a growing number of studies indicating the efficacy of nutritional approaches to help behaviourally at-risk children.


Subject(s)
5-Hydroxytryptophan/therapeutic use , Child Behavior Disorders/drug therapy , Glutamates/therapeutic use , Serotonin/metabolism , Adolescent , Adoption/psychology , Biomarkers/urine , Child , Child Behavior Disorders/etiology , Child Behavior Disorders/urine , Child, Preschool , Dietary Supplements , Female , Glutamates/urine , Humans , Male , Neurotransmitter Agents/therapeutic use , Neurotransmitter Agents/urine , Serotonin/urine , Treatment Outcome , gamma-Aminobutyric Acid/metabolism , gamma-Aminobutyric Acid/urine
17.
J Exp Med ; 190(10): 1493-504, 1999 Nov 15.
Article in English | MEDLINE | ID: mdl-10562323

ABSTRACT

Hematopoietic stem cell (HSC) self-renewal is a complicated process, and its regulatory mechanisms are poorly understood. Previous studies have identified tumor necrosis factor (TNF)-alpha as a pleiotropic cytokine, which, among other actions, prevents various hematopoietic progenitor cells from proliferating and differentiating in vitro. However, its role in regulating long-term repopulating HSCs in vivo has not been investigated. In this study, mice deficient for the p55 or the p75 subunit of the TNF receptor were analyzed in a variety of hematopoietic progenitor and stem cell assays. In older p55(-/-) mice (>6 mo), we identified significant differences in their hematopoietic system compared with age-matched p75(-/-) or wild-type counterparts. Increased marrow cellularity and increased numbers of myeloid and erythroid colony-forming progenitor cells (CFCs), paralleled by elevated peripheral blood cell counts, were found in p55-deficient mice. In contrast to the increased myeloid compartment, pre-B CFCs were deficient in older p55(-/-) mice. In addition, a fourfold decrease in the number of HSCs could be demonstrated in a competitive repopulating assay. Secondary transplantations of marrow cells from primary recipients of p55(-/-) marrow revealed impaired self-renewal ability of p55-deficient HSCs. These data show that, in vivo, signaling through the p55 subunit of the TNF receptor is essential for regulating hematopoiesis at the stem cell level.


Subject(s)
Antigens, CD/physiology , Hematopoiesis , Hematopoietic Stem Cells/physiology , Receptors, Tumor Necrosis Factor/physiology , Animals , Cell Cycle , Cell Division , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, Tumor Necrosis Factor, Type I , Receptors, Tumor Necrosis Factor, Type II
18.
Am J Transplant ; 10(1): 173-9, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19919660

ABSTRACT

Opportunistic infection remains the principal cause of mortality in allogeneic stem cell transplant recipients with active extensive chronic graft-versus-host disease. Human cytomegalovirus (HCMV) represents an important cause of disease in this setting and the toxicity of protracted and recurrent antiviral treatment together with eventual drug resistance represents a significant limitation to therapy. Although the expansion and adoptive transfer of HCMV-specific T cells from the healthy original donor can be an effective strategy to control viral replication, this is not possible when donors are seronegative or are subsequently inaccessible. Here we demonstrate for the first time, the successful expansion of HCMV-specific T cells from a seropositive transplant recipient of a seronegative graft with active HCMV disease and the long-term reconstitution of protective antiviral immunity following their adoptive transfer back into the patient.


Subject(s)
Cytomegalovirus Infections/immunology , Cytomegalovirus Infections/therapy , Cytomegalovirus/immunology , Immunotherapy, Adoptive/methods , Stem Cell Transplantation/adverse effects , T-Lymphocytes/immunology , T-Lymphocytes/virology , Adult , Amino Acid Sequence , Antigens, Viral/administration & dosage , Antigens, Viral/genetics , Base Sequence , Cytomegalovirus/genetics , Cytomegalovirus/isolation & purification , Cytomegalovirus Infections/etiology , DNA Primers/genetics , Humans , Male , Polymerase Chain Reaction , Transplantation, Homologous , Viral Load , Viral Proteins/administration & dosage , Viral Proteins/genetics , Viral Proteins/immunology
19.
Br J Dermatol ; 162(1): 152-8, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19796179

ABSTRACT

Background In 2006 a U.K. government White Paper recommended making NHS care in England more accessible by shifting services from secondary care into community settings. There is a shortage of contemporary activity data for U.K. dermatology units to allow benchmarking for service development. This study will not only provide useful comparative data for the future in Wales, but will also serve to highlight the impact of changes made in England. Objective To provide an overview of 1 week's dermatology outpatient activity for the whole of Wales. Methods All dermatology units in Wales collected data for 1 week in early 2007. The case mix, appropriateness of referral, requirement for surgery or second-line therapies and follow-up requirements were all determined. Results A total of 2142 patients were seen. Of new patients, 21% had skin cancer. Seventeen per cent of skin cancers had no diagnosis suggested by the general practitioner (GP) and 10% of basal cell carcinomas, 33% of squamous cell carcinomas and 17% of malignant melanomas were inappropriately diagnosed. In all, 26% of new patients had benign lesions, and this group caused the greatest diagnostic difficulty for GPs. Seventy-one per cent of these patients were diagnosed, reassured and discharged at their first visit without the need for biopsy or surgery. Thirty-seven per cent of new patients required surgery, of which 21% required complex intervention. Twenty-six per cent of follow-up patients were receiving second-line therapies. The new to follow-up ratio varied considerably according to diagnosis, the mean ratio being 1 : 0.21 for benign lesions through to 1 : 5.53 for psoriasis. This highlights the inappropriate nature of a 'one fits all' ratio. The majority of follow-up patients in secondary care required this level of input for monitoring of cancer, complex second-line therapies or surgery. Conclusions This study provides evidence to support logical planning of dermatological services and to assess the impact of proposed changes on different healthcare systems in the U.K.


Subject(s)
Delivery of Health Care/standards , Dermatology/standards , Family Practice/standards , Outpatient Clinics, Hospital , Referral and Consultation/standards , Skin Diseases/diagnosis , Carcinoma, Basal Cell/diagnosis , Carcinoma, Squamous Cell/diagnosis , Humans , Melanoma/diagnosis , Skin Neoplasms/diagnosis , Wales
20.
J Dairy Sci ; 93(11): 5309-17, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20965347

ABSTRACT

Holstein rumen-cannulated cows [n=7; initial body weight (BW) 640.56±71.43 kg] were fed a corn silage basal diet with 1 of 3 concentrates (C=control; P10=10% pigeon peas; P20=20% pigeon peas). Cows were randomly assigned to treatments in a replicated 3×3 Latin square and individually fed using Calan gates. Each experimental period was 21 d with 7 d for adaption and 14 d for sample collection. Ruminal fluid samples were taken the last day of each experimental period and analyzed for pH, ammonia, long-chain fatty acids, and volatile fatty acids (VFA). Consecutive a.m. and p.m. milk samples were taken during the last 2 wk of the 21-d period and analyzed for fat, protein, long-chain fatty acids, and somatic cell count. Dry matter intake (kg/d) was reduced during the second period and was greater for P10 diets. Milk protein was greater for cows fed P20 compared with P10. Energy-corrected milk was greater for cows fed the control diet compared with P10. Treatment had no effect on milk yield. Ruminal fluid pH decreased over sampling times; however, pH remained at or above 5.5. Diets did not affect ruminal fluid pH; however, pH was different for sampling periods. Ruminal ammonia decreased until 8h postfeeding at which time it peaked consistent with changes in ammonia concentrations that usually peak 3 to 5h postfeeding on diets high in plant proteins. Dietary treatments altered ruminal fluid VFA with reduced concentrations of acetate and greater concentrations of propionate for control diet, resulting in reduced acetate:propionate ratio. Isobutyrate exhibited an hour by treatment interaction, in which isobutyrate decreased until 8h postfeeding and then tended to be greater for P10 than for other treatments. Animals fed the P10 diet had greater concentrations of ruminal isovalerate. Ruminal cis-9,trans-11 and trans-10,cis-12 conjugated linoleic acid (CLA) isomers were not affected by dietary treatments. The P10 diet had greatest ruminal synthesis of cis-9,trans-11, but control cows had greatest ruminal synthesis of trans-10,cis-12. Milk CLA isomers were similar among treatments. Trends were observed for greater cis-9,trans-11 and trans-10,cis-12 for the P10 diet. Pigeon peas may be used as a protein supplement in dairy diets without affecting milk production, dry matter intake, or ruminal environment when they replace corn and soybean meal.


Subject(s)
Cajanus/metabolism , Cattle/physiology , Lactation/physiology , Rumen/metabolism , Animal Nutritional Physiological Phenomena , Animals , Cattle/metabolism , Dietary Supplements , Female , Linoleic Acid/analysis , Milk/chemistry , Milk/metabolism , Rumen/chemistry , Silage , Zea mays/metabolism
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