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1.
Appl Ergon ; 119: 104311, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38763088

ABSTRACT

To optimise soldier protection within body armour systems, knowledge of the boundaries of essential thoraco-abdominal organs is necessary to inform coverage requirements. However, existing methods of organ boundary identification are costly and time consuming, limiting widespread adoption for use on soldier populations. The aim of this study was to evaluate a novel method of using 3D organ models to identify essential organ boundaries from low dose planar X-rays and 3D external surface scans of the human torso. The results revealed that, while possible to reconstruct 3D organs using template 3D organ models placed over X-ray images, the boundary data (relating to the size and position of each organ) obtained from the reconstructed organs differed significantly from MRI organ data. The magnitude of difference varied between organs. The most accurate anatomical boundaries were the left, right, and inferior boundaries of the heart, and lateral boundaries for the liver and spleen. Visual inspection of the data demonstrated that 11 of 18 organ models were successfully integrated within the 3D space of the participant's surface scan. These results suggest that, if this method is further refined and evaluated, it has potential to be used as a tool for estimating body armour coverage requirements.


Subject(s)
Abdomen , Anthropometry , Imaging, Three-Dimensional , Liver , Magnetic Resonance Imaging , Humans , Anthropometry/methods , Male , Liver/diagnostic imaging , Liver/anatomy & histology , Adult , Abdomen/diagnostic imaging , Abdomen/anatomy & histology , Thorax/diagnostic imaging , Thorax/anatomy & histology , Spleen/diagnostic imaging , Spleen/anatomy & histology , Protective Clothing , Torso/diagnostic imaging , Military Personnel , Heart/diagnostic imaging , Heart/anatomy & histology , Young Adult , Female
2.
J Appl Res Intellect Disabil ; 37(2): e13162, 2024 Mar.
Article in English | MEDLINE | ID: mdl-37816696

ABSTRACT

BACKGROUND: Endings in therapy are discussed widely in mainstream literature, however, there is only a small amount of research that considers endings in therapy for people with intellectual disabilities. METHODS: Eight therapists were interviewed about their experience of ending therapy with people with intellectual disabilities. Interviews were analysed using Interpretative Phenomenological Analysis (IPA). RESULTS: Four superordinate themes associated with endings that go well were identified: 'recognising', 'readying', 'reframing' and reflecting', with a fifth theme reflecting endings that were less successful. Participants worked hard to offer transformative experiences of endings and an overarching 'super-superordinate' theme of 'facilitating transformative endings' encompassed the findings. CONCLUSIONS: Endings are a multi-faceted component of psychological therapy with people with intellectual disabilities and are significant for both client and therapist. We discuss implications for therapy adaptations and future research.


Subject(s)
Intellectual Disability , Humans , Intellectual Disability/psychology , Allied Health Personnel , Qualitative Research
3.
Appl Ergon ; 106: 103891, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36113184

ABSTRACT

To optimise fit and protection of body armour systems, knowledge of the location of thoracoabdominal organ boundaries is required. The aims of this study were (i) determine the effect of sex on essential and desirable thoracoabdominal organ boundaries, and (ii) compare essential thoracoabdominal organ boundaries with small and large hard ballistic plate sizes from the National Institute of Justice (NIJ) and determine if coverage requirements differ between sexes. 33 males and 33 females underwent supine magnetic resonance imaging of their thoracoabdominal organs. Male participants on average displayed more laterally and inferiorly positioned essential and desirable organ boundaries than females. Based on NIJ plate sizes, insufficient coverage of essential organs was identified for male and female participants. A greater range of body armour sizes and designs that better cater to the diverse anatomy of soldier populations is warranted, but must be considered in the context of ergonomic and performance implications.


Subject(s)
Military Personnel , Protective Clothing , Female , Humans , Male , Body Size , Sex Factors
5.
ACS Chem Neurosci ; 13(17): 2658-2665, 2022 09 07.
Article in English | MEDLINE | ID: mdl-35946788

ABSTRACT

Multiple sclerosis (MS) is an inflammatory disease characterized by damage to the myelin sheath surrounding axons in the central nervous system. While the exact mechanism of this destruction is unknown, excess nitric oxide (NO) and adenosine triphosphate (ATP) have been measured in tissues and fluids obtained from people with MS. Here, incubation of interferon-beta (IFN-ß), an MS drug with an unknown mechanism of action, with red blood cells (RBCs) obtained from people with MS provide evidence of a potential hypermetabolic state in the MS RBC that is decreased with IFN-ß intervention. Specifically, binding of all three components of an albumin/C-peptide/Zn2+ complex to MS RBCs was significantly increased in comparison to control RBCs. For example, the binding of C-peptide to MS RBCs was significantly increased (3.4 ± 0.1 nM) compared to control RBCs (1.6 ± 0.2 nM). However, C-peptide binding to MS RBCs was reduced to a value (1.6 ± 0.3 nM) statistically equal to that of control RBCs in the presence of 2 nM IFN-ß. Similar trends were measured for albumin and Zn2+ binding to RBCs when in the presence of IFN-ß. RBC function was also affected by incubation of cells with IFN-ß. Specifically, RBC-derived ATP and measurable membrane GLUT1 were both significantly decreased (56 and 24%, respectively) in the presence of IFN-ß. Collectively, our results suggest that IFN-ß inhibits albumin binding to the RBC, thereby reducing its ability to deliver ligands such as C-peptide and Zn2+ to the cell and normalizing the basal hypermetabolic state.


Subject(s)
Interferon-beta , Multiple Sclerosis , Adenosine Triphosphate/metabolism , Albumins/metabolism , C-Peptide/metabolism , Erythrocytes/metabolism , Humans , Interferon-beta/metabolism , Multiple Sclerosis/drug therapy , Multiple Sclerosis/metabolism
6.
Musculoskelet Surg ; 106(1): 59-68, 2022 Mar.
Article in English | MEDLINE | ID: mdl-32638225

ABSTRACT

INTRODUCTION: While lung is the most common site of metastasis, bone metastasis of soft tissue sarcoma is a part of the natural history affecting the prognosis of these patients. To date, no studies have analyzed the histologic subtypes more likely to metastasize to bone, the risk factors for bone metastasis at initial presentation, or the effect that bone metastasis has on the survival of these patients. MATERIAL/METHODS: Patients were identified from the Surveillance, Epidemiology and End Results database with primary extremity STS between 2010 and 2015. Risk factors for early bone metastasis, survival based on different sites of metastasis, and prognostic factors of survival were analyzed. RESULTS: Among 8,234 STS, 2.2% (n = 180) presented with skeletal metastasis. Bone metastasis was more likely when regional lymph nodes were involved (OR = 4.48, p = 0.008). Deep and moderate or high-grade sarcomas had 5-12-fold tendency to present with bone and lung metastasis (p = 0.046, 0.006, 0.030, respectively). The 5-year survival rate was 41.2% (26.9-54.9%) for isolated bone metastasis and 32.9% (21.2-45.1%) for patients with bone and lung metastasis. Resection of the primary sarcoma was the only significant predictor of survival (HR = 0.44, p = 0.021) for patients with bone metastasis. CONCLUSION: High tumor grade, deep location to fascia and regional lymph node metastasis are significant risk factors for skeletal metastasis at diagnosis of an extremity STS. While neither systemic chemotherapy nor radiotherapy of the primary sarcoma has a significant influence on survival in the presence of bone metastasis, radical resection of the primary STS is associated with increased survival.


Subject(s)
Sarcoma , Soft Tissue Neoplasms , Extremities/pathology , Humans , Prognosis , Registries , Retrospective Studies , Risk Factors , Sarcoma/drug therapy , Soft Tissue Neoplasms/pathology , Survival Analysis
7.
J Hosp Infect ; 108: 189-196, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33259882

ABSTRACT

BACKGROUND: Understanding how severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is spread within the hospital setting is essential in order to protect staff, implement effective infection control measures, and prevent nosocomial transmission. METHODS: The presence of SARS-CoV-2 in the air and on environmental surfaces around hospitalized patients, with and without respiratory symptoms, was investigated. Environmental sampling was undertaken within eight hospitals in England during the first wave of the coronavirus disease 2019 outbreak. Samples were analysed using reverse transcription polymerase chain reaction (PCR) and virus isolation assays. FINDINGS: SARS-CoV-2 RNA was detected on 30 (8.9%) of 336 environmental surfaces. Cycle threshold values ranged from 28.8 to 39.1, equating to 2.2 x 105 to 59 genomic copies/swab. Concomitant bacterial counts were low, suggesting that the cleaning performed by nursing and domestic staff across all eight hospitals was effective. SARS-CoV-2 RNA was detected in four of 55 air samples taken <1 m from four different patients. In all cases, the concentration of viral RNA was low and ranged from <10 to 460 genomic copies/m3 air. Infectious virus was not recovered from any of the PCR-positive samples analysed. CONCLUSIONS: Effective cleaning can reduce the risk of fomite (contact) transmission, but some surface types may facilitate the survival, persistence and/or dispersal of SARS-CoV-2. The presence of low or undetectable concentrations of viral RNA in the air supports current guidance on the use of specific personal protective equipment for aerosol-generating and non-aerosol-generating procedures.


Subject(s)
COVID-19/diagnosis , Disinfection/statistics & numerical data , Health Facilities/statistics & numerical data , SARS-CoV-2/genetics , Aerosols , COVID-19/epidemiology , COVID-19/transmission , COVID-19/virology , Cross Infection/prevention & control , Cross Infection/transmission , Disease Outbreaks/prevention & control , Disinfection/methods , England/epidemiology , Female , Fomites/statistics & numerical data , Fomites/virology , Health Personnel/education , Hospitals/statistics & numerical data , Humans , Infection Control/methods , Male , Personal Protective Equipment/standards , RNA, Viral/genetics , RNA, Viral/isolation & purification , Reverse Transcriptase Polymerase Chain Reaction/methods , SARS-CoV-2/isolation & purification
8.
Sci Rep ; 10(1): 17493, 2020 10 15.
Article in English | MEDLINE | ID: mdl-33060722

ABSTRACT

People with type 1 diabetes (T1D) require exogenous administration of insulin, which stimulates the translocation of the GLUT4 glucose transporter to cell membranes. However, most bloodstream cells contain GLUT1 and are not directly affected by insulin. Here, we report that C-peptide, the 31-amino acid peptide secreted in equal amounts with insulin in vivo, is part of a 3-component complex that affects red blood cell (RBC) membranes. Multiple techniques were used to demonstrate saturable and specific C-peptide binding to RBCs when delivered as part of a complex with albumin. Importantly, when the complex also included Zn2+, a significant increase in cell membrane GLUT1 was measured, thus providing a cellular effect similar to insulin, but on a transporter on which insulin has no effect.


Subject(s)
C-Peptide/administration & dosage , Erythrocytes/metabolism , Glucose Transporter Type 1/metabolism , Serum Albumin, Bovine/chemistry , Zinc/administration & dosage , Adenosine Triphosphate/chemistry , Animals , Biological Transport , Cattle , Cell Membrane/metabolism , Diabetes Mellitus, Type 1/metabolism , Gene Expression Regulation , Glucose/metabolism , Humans , Insulin/metabolism
9.
Tech Coloproctol ; 24(7): 671-684, 2020 07.
Article in English | MEDLINE | ID: mdl-32236745

ABSTRACT

BACKGROUND: The aim of this study was to analyse local single-institution data and perform a systematic review of the literature to calculate precise risk estimates of rectal stump-related morbidity and mortality following subtotal colectomy in patients with inflammatory bowel disease (IBD), including Crohn's colitis, ulcerative colitis and indeterminate colitis. METHODS: Institutional information systems were interrogated to obtain local patient data. A systematic review of MEDLINE and EMBASE was performed to identify relevant articles. Fixed-effects or random-effects meta-analysis of proportions was performed to calculate pooled incidence estimates, including local data. RESULTS: Sixty-one patients were included locally and all had their rectal stump closed intra-abdominally. Four patients (8.3%) had a rectal stump perforation and 30-day mortality was 0. Fourteen papers were included in our review alongside local data, with a total of 1330 patients included. Pooled mortality was 1.7% (95% confidence interval, CI 1.0-2.8), pooled incidence of pelvic abscess/sepsis, stump leak and wound infection was 5.7% (95% CI 4.4-7.3), 4.9% (95% CI 3.7-6.6) and 11.3% (95% CI 7.8-16), respectively. Subcutaneous placement of the stump was associated with the highest incidence of stump leak (12.6%, 95% CI 8.3-18.6), and closure of the stump with both staples and suture was associated with the highest incidence of pelvic abscess (11.1%, 95% CI 5.8-20.3). Mortality and the incidence of wound infection were similar across stump closure techniques. There was evidence suggesting considerable heterogeneity and publication bias among studies. CONCLUSIONS: This study provides estimates of morbidity associated with the rectal stump after subtotal colectomy for IBD. A closed intra-abdominal stump seems to be associated with the highest rate of pelvic abscess/sepsis. Further work in form of an international collaborative project would allow individual patient data analysis and identification of risk factors for complications.


Subject(s)
Colitis, Ulcerative , Colitis , Inflammatory Bowel Diseases , Cohort Studies , Colectomy , Colitis/surgery , Colitis, Ulcerative/surgery , Humans , Inflammatory Bowel Diseases/surgery , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Rectum/surgery
10.
J Appl Res Intellect Disabil ; 33(5): 839-855, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32107821

ABSTRACT

BACKGROUND: People with intellectual disability experience a higher prevalence of dementia, at an earlier age, than the general population. The aim of this review was to establish the psychological interventions and outcomes for individuals with intellectual disability and dementia. METHODS: A search of eight electronic databases and reference lists of all included articles was conducted using PRISMA guidelines. Data were synthesized using an integrative method. RESULTS: Initial searching produced 2,331 papers. Twenty-one studies met the inclusion criteria. Interventions were deductively categorized into behavioural, systemic and therapeutic. All studies reported positive findings for individuals and for the systems which support them, but limited by methodological issues and neglect of the direct experience and impact on individuals themselves. CONCLUSIONS: The findings are discussed in relation to the wider literature and evidence base. Future research should aim to adopt methodologically robust designs that are inclusive of the individual experience of people with intellectual disability.


Subject(s)
Dementia , Intellectual Disability , Humans , Intellectual Disability/therapy , Prevalence , Psychosocial Intervention
11.
Vet Parasitol ; 243: 226-234, 2017 Aug 30.
Article in English | MEDLINE | ID: mdl-28807298

ABSTRACT

Haemaphysalis longicornis is the only species of tick present in New Zealand which infests livestock and is also the only competent vector for Theileria orientalis. Since 2012, New Zealand has suffered from an epidemic of infectious bovine anaemia associated with T. orientalis, an obligate intracellular protozoan parasite of cattle and buffaloes. The aim of this study was to predict the spatial distribution of habitat suitability of New Zealand for the tick H. longicornis using a simple rule-based climate envelope model, to validate the model against published data and use the validated model to project an expansion in habitat suitability for H. longicornis under two alternative climate change scenarios for the periods 2046-2065 and 2081-2100, relative to the climate of 1981-2010. A rule-based climate envelope model was developed based on the environmental requirements for off-host tick survival. The resulting model was validated against a maximum entropy environmental niche model of environmental suitability for T. orientalis transmission and against a H. longicornis occurrence map. Validation was completed using the I-similarity statistic and by linear regression. The H. longicornis climate envelope model predicted that 75% of cattle farms in the North Island, 3% of cattle farms in the South Island and 54% of cattle farms in New Zealand overall have habitats potentially suitable for the establishment of H. longicornis. The validation methods showed an acceptable level of agreement between the envelope model and published data. Both of the climate change scenarios, for each of the time periods, projected only slight to moderate increases in the average farm habitat suitability scores for all the South Island regions. However, only for the West Coast, Marlborough, Tasman, and Nelson regions did these increases in environmental suitability translate into an increased proportion of cattle farms with low or high H. longicornis habitat suitability. These results will have important implications for the geographical progression of Theileria-associated bovine anaemia (TABA) in New Zealand and will also be of interest to Haemaphysalis longicornis researchers in Australia, Japan, Korea and New Zealand.


Subject(s)
Animal Distribution , Climate Change , Ecosystem , Ixodidae/physiology , Models, Biological , Animals , Forecasting , New Zealand
12.
Top Companion Anim Med ; 32(3): 104-108, 2017 Sep.
Article in English | MEDLINE | ID: mdl-29291771

ABSTRACT

Some cats develop vomiting or diarrhea during administration of some antibiotics such as amoxicillin-clavulanate but how often this occurs and the severity of disease is generally unknown. In people, one of the accepted indications for the use of probiotics is to attempt and lessen antibiotic-associated diarrhea. Enterococcus faecium strain SF68 (SF68; Purina® ProPlan® Veterinary Diets; FortiFlora™ Probiotic Supplement) is a commercially available probiotic available in many countries that has been shown to lessen diarrhea rates in cats housed in animal shelters. The objectives of this study were to describe the gastrointestinal abnormalities (clinical and microbiome) associated with the administration of amoxicillin-clavulanate to cats and to determine whether feeding SF68 could ameliorate those abnormalities. Laboratory reared domestic cats were administered amoxicillin-clavulanate for 7 days with or without SF68 for 14 days and monitored for vomiting and diarrhea and for changes in the gastrointestinal microbiome before and after antibiotic administration. Fecal scores > 5 on a 7-point scale were detected in 9 of 13 cats (69.2%) fed SF68 compared to 12 of 14 cats fed the placebo (85.7%). Fecal scores of 7 were only detected in the placebo group and when total diarrhea scores were compared between groups for days 1-11, the cats fed SF68 were statistically lower (P = 0.0058). Administration of amoxicillin-clavulanate led to decreased microbiome diversity, but differences between cats fed SF68 or the placebo were not detected. The results show administering amoxicillin-clavulanate orally to cats commonly induces diarrhea and alters the gastrointestinal microbiome, and that feeding the probiotic SF68 can lessen some associated clinical abnormalities.


Subject(s)
Cat Diseases/drug therapy , Diarrhea/veterinary , Enterococcus faecium , Probiotics/therapeutic use , Amoxicillin-Potassium Clavulanate Combination/administration & dosage , Amoxicillin-Potassium Clavulanate Combination/therapeutic use , Animals , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/therapeutic use , Cat Diseases/microbiology , Cats , Diarrhea/drug therapy , Dietary Supplements , Drug Administration Schedule , Feces/microbiology , Female , Male , Microbiota , Probiotics/administration & dosage , Treatment Outcome
13.
Vet Parasitol ; 224: 82-91, 2016 Jul 15.
Article in English | MEDLINE | ID: mdl-27270395

ABSTRACT

The tick-borne haemoparasite Theileria orientalis is the most important infectious cause of anaemia in New Zealand cattle. Since 2012 a previously unrecorded type, T. orientalis type 2 (Ikeda), has been associated with disease outbreaks of anaemia, lethargy, jaundice and deaths on over 1000 New Zealand cattle farms, with most of the affected farms found in the upper North Island. The aim of this study was to model the relative environmental suitability for T. orientalis transmission throughout New Zealand, to predict the proportion of cattle farms potentially suitable for active T. orientalis infection by region, island and the whole of New Zealand and to estimate the average relative environmental suitability per farm by region, island and the whole of New Zealand. The relative environmental suitability for T. orientalis transmission was estimated using the Maxent (maximum entropy) modelling program. The Maxent model predicted that 99% of North Island cattle farms (n=36,257), 64% South Island cattle farms (n=15,542) and 89% of New Zealand cattle farms overall (n=51,799) could potentially be suitable for T. orientalis transmission. The average relative environmental suitability of T. orientalis transmission at the farm level was 0.34 in the North Island, 0.02 in the South Island and 0.24 overall. The study showed that the potential spatial distribution of T. orientalis environmental suitability was much greater than presumed in the early part of the Theileria associated bovine anaemia (TABA) epidemic. Maximum entropy offers a computer efficient method of modelling the probability of habitat suitability for an arthropod vectored disease. This model could help estimate the boundaries of the endemically stable and endemically unstable areas for T. orientalis transmission within New Zealand and be of considerable value in informing practitioner and farmer biosecurity decisions in these respective areas.


Subject(s)
Cattle Diseases/epidemiology , Cattle Diseases/transmission , Environment , Models, Biological , Theileriasis/epidemiology , Theileriasis/transmission , Animals , Cattle , Entropy , New Zealand , Theileria/physiology
14.
Oncogene ; 34(25): 3296-304, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25151967

ABSTRACT

Isoprenylcysteine carboxylmethyltransferase (Icmt) catalyzes the last of the three-step posttranslational protein prenylation process for the so-called CaaX proteins, which includes many signaling proteins, such as most small GTPases. Despite extensive studies on Icmt and its regulation of cell functions, the mechanisms of much of the impact of Icmt on cellular functions remain unclear. Our recent studies demonstrated that suppression of Icmt results in induction of autophagy, inhibition of cell growth and inhibition of proliferation in various cancer cell types, prompting this investigation of potential metabolic regulation by Icmt. We report here the findings that Icmt inhibition reduces the function of mitochondrial oxidative phosphorylation in multiple cancer cell lines. In-depth oximetry analysis demonstrated that functions of mitochondrial complex I, II and III are subject to Icmt regulation. Consistently, Icmt inhibition decreased cellular ATP and depleted critical tricarboxylic acid cycle metabolites, leading to suppression of cell anabolism and growth, and marked autophagy. Several different approaches demonstrated that the impact of Icmt inhibition on cell proliferation and viability was largely mediated by its effect on mitochondrial respiration. This previously unappreciated function of Icmt, which can be therapeutically exploited, likely has a significant role in the impact of Icmt on tumorigenic processes.


Subject(s)
Mitochondria/metabolism , Protein Methyltransferases/metabolism , AMP-Activated Protein Kinases/metabolism , Carcinogenesis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Respiration/drug effects , Cell Survival/drug effects , Electron Transport Chain Complex Proteins/metabolism , Energy Metabolism/drug effects , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Humans , Indoles/pharmacology , Mitochondria/drug effects , Mitochondria/enzymology , Protein Methyltransferases/antagonists & inhibitors
15.
Clin Genet ; 86(2): 181-4, 2014 Aug.
Article in English | MEDLINE | ID: mdl-25180401

ABSTRACT

This study examined the relationship between the fragile X premutation and restless legs syndrome (RLS). Demographic, medical history and survey responses related to sleep were collected from 213 participants (127 carriers and 86 age matched controls). Subjects were asked about the presence of the four formal diagnostic criteria for RLS. Individuals with the premutation were 1.9 times as likely to meet criteria for RLS (95% CI 1.1­3.2, p=0.025) as controls. Premutation carriers with RLS also experienced significantly worse symptoms than matched controls with adjusted mean scores of 15.1±8.8 vs 7.9±4.4, respectively on the International Restless Legs Scale (IRLS). As markers for domains of sleep disturbance, all subjects completed the Epworth Sleepiness Scale (ESS), the Insomnia Severity Index (ISA) and the Pittsburgh Sleep Quality Index (PSQI). Premutation carriers demonstrated significantly more pathology on these tests except for the ESS where there was a trend towards increased daytime sleepiness in carriers. RLS joins a host of other conditions that should be carefully screened for in those carrying the fragile X premutation and sleep should be a focus for clinicians providing care to them.


Subject(s)
Fragile X Mental Retardation Protein/genetics , Mutation/genetics , Restless Legs Syndrome/epidemiology , Restless Legs Syndrome/genetics , Sleep , Age Factors , Case-Control Studies , Demography , Female , Humans , Male , Middle Aged , Prevalence , Restless Legs Syndrome/physiopathology , Severity of Illness Index , Sleep Initiation and Maintenance Disorders/genetics
16.
Clin Exp Immunol ; 176(3): 341-50, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24528105

ABSTRACT

Interleukin (IL)-17A is increased both in serum and in kidney biopsies from patients with lupus nephritis, but direct evidence of pathogenicity is less well established. Administration of pristane to genetically intact mice results in the production of autoantibodies and proliferative glomerulonephritis, resembling human lupus nephritis. These studies sought to define the role of IL-17A in experimental lupus induced by pristane administration. Pristane was administered to wild-type (WT) and IL-17A(-/-) mice. Local and systemic immune responses were assessed after 6 days and 8 weeks, and autoimmunity, glomerular inflammation and renal injury were measured at 7 months. IL-17A production increased significantly 6 days after pristane injection, with innate immune cells, neutrophils (Ly6G(+)) and macrophages (F4/80(+)) being the predominant source of IL-17A. After 8 weeks, while systemic IL-17A was still readily detected in WT mice, the levels of proinflammatory cytokines, interferon (IFN)-γ and tumour necrosis factor (TNF) were diminished in the absence of endogenous IL-17A. Seven months after pristane treatment humoral autoimmunity was diminished in the absence of IL-17A, with decreased levels of immunoglobulin (Ig)G and anti-dsDNA antibodies. Renal inflammation and injury was less in the absence of IL-17A. Compared to WT mice, glomerular IgG, complement deposition, glomerular CD4(+) T cells and intrarenal expression of T helper type 1 (Th1)-associated proinflammatory mediators were decreased in IL-17A(-/-) mice. WT mice developed progressive proteinuria, but functional and histological renal injury was attenuated in the absence of IL-17A. Therefore, IL-17A is required for the full development of autoimmunity and lupus nephritis in experimental SLE, and early in the development of autoimmunity, innate immune cells produce IL-17A.


Subject(s)
Autoimmunity , Interleukin-17/metabolism , Lupus Nephritis/immunology , Lupus Nephritis/metabolism , Animals , Autoantibodies/immunology , Complement C3/immunology , Complement C3/metabolism , Cytokines/metabolism , Disease Models, Animal , Glomerulonephritis/genetics , Glomerulonephritis/immunology , Glomerulonephritis/pathology , Humans , Immunity, Humoral/drug effects , Immunity, Humoral/genetics , Immunity, Innate/drug effects , Immunity, Innate/genetics , Immunoglobulin G/immunology , Immunoglobulin G/metabolism , Interleukin-17/genetics , Kidney Glomerulus/immunology , Kidney Glomerulus/metabolism , Kidney Glomerulus/pathology , Lupus Nephritis/chemically induced , Mice , Mice, Knockout , Spleen/cytology , Spleen/immunology , Terpenes/adverse effects
17.
J Chem Phys ; 135(16): 165102, 2011 Oct 28.
Article in English | MEDLINE | ID: mdl-22047267

ABSTRACT

In stochastic models of chemically reacting systems that contain bimolecular reactions, the dynamics of the moments of order up to n of the species populations do not form a closed system, in the sense that their time-derivatives depend on moments of order n + 1. To close the dynamics, the moments of order n + 1 are generally approximated by nonlinear functions of the lower order moments. If the molecule counts of some of the species have a high probability of becoming zero, such approximations may lead to imprecise results and stochastic simulation is the only viable alternative for system analysis. Stochastic simulation can produce exact realizations of chemically reacting systems, but tends to become computationally expensive, especially for stiff systems that involve reactions at different time scales. Further, in some systems, important stochastic events can be very rare and many simulations are necessary to obtain accurate estimates. The computational cost of stochastic simulation can then be prohibitively large. In this paper, we propose a novel method for estimating the moments of chemically reacting systems. The method is based on closing the moment dynamics by replacing the moments of order n + 1 by estimates calculated from a small number of stochastic simulation runs. The resulting stochastic system is then used in an extended Kalman filter, where estimates of the moments of order up to n, obtained from the same simulation, serve as outputs of the system. While the initial motivation for the method was improving over the performance of stochastic simulation and moment closure methods, we also demonstrate that it can be used in an experimental setting to estimate moments of species that cannot be measured directly from time course measurements of the moments of other species.


Subject(s)
Models, Chemical , Algorithms , Computer Simulation , Models, Biological , Stochastic Processes
18.
Clin Exp Immunol ; 166(2): 227-34, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21985369

ABSTRACT

Experimental crescentic glomerulonephritis is driven by systemic cellular immune responses. A pathogenic role for T helper type 1 (Th1) and Th17 cells is well established. T-bet, a key transcription factor required for Th1 lineage commitment, and retinoic acid-related orphan receptor-γt (Rorγt), a key Th17 transcription factor, are required for full expression of disease. Similarly, several Th1- and Th17-associated cytokines have been implicated in disease augmentation. The role of Th2 cells in the disease is less clear, although Th2-associated cytokines, interleukin (IL)-4 and IL-10, are protective. We sought to determine the role of signal transducer and activation of transcription 6 (STAT6), a key regulator of Th2 responses, in experimental crescentic glomerulonephritis. Compared to wild-type mice, histological and functional renal injury was enhanced significantly in STAT6(-/-) mice 21 days after administration of sheep anti-mouse glomerular basement membrane globulin. Consistent with the enhanced renal injury, both Th1 and Th17 nephritogenic immune responses were increased in STAT6(-/-) mice. Conversely, production of IL-5, a key Th2-associated cytokine, was decreased significantly in STAT6(-/-) mice. Early in the disease process systemic mRNA expression of T-bet and Rorγ was increased in STAT6(-/-) mice. We conclude that STAT6 is required for attenuation of Th1 and Th17 nephritogenic immune responses and protection from crescentic glomerulonephritis.


Subject(s)
Glomerulonephritis/immunology , STAT6 Transcription Factor/metabolism , Th1 Cells/immunology , Th17 Cells/immunology , Animals , Cytokines/immunology , Cytokines/metabolism , Glomerulonephritis/chemically induced , Kidney/immunology , Kidney/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , RNA, Messenger/biosynthesis , STAT6 Transcription Factor/biosynthesis , T-Box Domain Proteins/metabolism
19.
J Autoimmun ; 35(4): 291-8, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20810248

ABSTRACT

Systemic lupus erythematosus is a common autoimmune disease, with kidney involvement a serious complication associated with poor prognosis. Humoral immune responses constitute the hallmark of disease, however T helper cells are required for the generation of autoantibodies, as well as the induction and progression of renal injury. Administration of pristane to genetically intact mice results in the development of hypergammaglobulinaemia with the production of lupus like autoantibodies and proliferative glomerulonephritis, with similarities to human lupus nephritis. TLRs are intricately linked to the development of autoimmunity and are involved in the development of lupus nephritis. We injected wild type, TLR9-/- and TLR4-/- mice with pristane and assessed cellular and humoral autoimmunity and renal injury, 8 months later. TLR9-/- mice demonstrated a predominant decrease in Th1 cytokine production which resulted in decreased anti-RNP antibody levels, while anti-dsDNA levels remained intact. Compared to wild type mice treated with pristane, functional and histological renal injury and glomerular immunoglobulin and complement deposition was decreased in TLR9-/- mice. TLR4-/- mice demonstrated a global decrease in both Th1, IFNγ, and Th17 associated IL-17A and IL-6 cytokine production. Autoantibody levels of anti-dsDNA and anti-RNP were both decreased. Renal injury was attenuated in TLR4-/- mice which demonstrated less glomerular immunoglobulin and complement deposition. These results demonstrate that both TLR9 and TLR4 are required for 'full-blown' autoimmunity and organ injury in experimental lupus induced by pristane.


Subject(s)
Autoantibodies/metabolism , Kidney/metabolism , Lupus Erythematosus, Systemic/immunology , Toll-Like Receptor 4/metabolism , Toll-Like Receptor 9/metabolism , Animals , Autoantibodies/genetics , Autoimmunity/genetics , Cells, Cultured , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Humans , Kidney/immunology , Kidney/pathology , Lupus Erythematosus, Systemic/chemically induced , Lupus Erythematosus, Systemic/pathology , Lupus Erythematosus, Systemic/physiopathology , Lupus Nephritis , Mice , Mice, Inbred C57BL , Mice, Knockout , Terpenes/administration & dosage , Th1 Cells/immunology , Toll-Like Receptor 4/genetics , Toll-Like Receptor 9/genetics
20.
Am J Transplant ; 8(8): 1755-8, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18557738

ABSTRACT

Calcium oxalate (CaOx) deposition in the renal allograft is an under recognized and important cause of acute tubular injury and early allograft dysfunction. We present a case of late transplant dysfunction due to acute oxalate nephropathy. The patient presented with diarrhea and deteriorating graft function, and a diagnosis of enteric hyperoxaluria secondary to pancreatic insufficiency was made. This had occurred, as the patient had been noncompliant with his pancreatic enzyme replacement therapy. Treatment to reduce his circulating oxalate load was initiated, including twice-daily hemodialysis, low fat and oxalate diet and appropriate administration of pancreatic enzyme supplements. Graft function subsequently recovered. The possibility of fat malabsorption leading to enteric hyperoxaluria should be considered in renal graft recipients presenting with loose stools and graft dysfunction.


Subject(s)
Acute Kidney Injury/etiology , Calcium Oxalate/adverse effects , Exocrine Pancreatic Insufficiency/complications , Hyperoxaluria/complications , Acute Disease , Aged , Humans , Hyperoxaluria/etiology , Kidney Transplantation , Male , Renal Dialysis , Treatment Outcome
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