Memory T cells: total recall or just a sense of déjà vu?
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Animals↗
Biomedical subjects
R Phillips
Publications and source records attributed to R Phillips.
Effect of HLA class II genotype on T helper lymphocyte responses and viral control in hepatitis C virus infection.
Hepatitis C virus (HCV) infection is very common worldwide, but has a broad range of outcomes. A minority of patients are able to clear infection spontaneously, and this is thought to be due to the emergence and maintenance of effective cell-mediated immunity, particularly CD4+ T lymphocyte responses. Furthermore, genetic studies have indicated that HLA class II genotype strongly influences the outcome of infection. We have therefore investigated the influence of the protective HLA class II haplotype (DQB1*0301, which is in tight linkage disequilibrium with DRB1*1101) on the CD4+ T lymphocyte responses to HCV. We observe a strong association between this genotype and maintenance of a multispecific CD4+ T helper response. The effect on T helper responses was also maintained after combination interferon-alpha/ribavirin therapy, although the latter influenced the pattern of viral antigens to which patients responded. This is the first disease in which an association of HLA genotype with clinical outcome has been linked to an alteration of the immunological phenotype. The selection of protective peptides in those with the favourable HLA class II genotype may point in the direction of suitable vaccine candidates.
Adult↗
Local methods of treatment of rectal cancer.
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Letter↗
Comparison of cross-sectional renal function measurements in African Americans with hypertensive nephrosclerosis and of primary formulas to estimate glomerular filtration rate.
Renal function measurements were obtained in 1,703 African Americans with presumed hypertensive nephrosclerosis who were screened for entry into the African-American Study of Hypertension and Kidney Disease (AASK). We examined the effect of race on relationships involving renal variables by comparing African Americans enrolled into the AASK with non-African Americans enrolled into the Modification of Diet in Renal Disease (MDRD) study. We examined the effect of gender on renal variables by comparing African American men and women. We compared various methods for estimating glomerular filtration rate (GFR) with iodine 125-labeled ((125)I)-iothalamate GFR. AASK data were also used to derive a new formula for estimating GFR in African Americans. After adjusting for age, sex, and baseline GFR, African American patients on the AASK study were heavier and had larger body surface areas and body mass indices than either MDRD African Americans or non-African Americans. African Americans had greater serum creatinine levels and urinary creatinine excretions for any given level of GFR. Mean GFR was greater in African American men than African American women (59.7 versus 51.7 mL/min/1.73 m(2)), although serum creatinine levels were also greater in men (1.91 versus 1.73 mg/dL). Seventy-eight percent of women with serum creatinine levels between 1.2 and 1.5 mg/dL had GFRs less than 65 mL/min/1.73 m(2). For African Americans in the AASK, GFR was overestimated by the 24-hour creatinine clearance and underestimated by the Cockcroft-Gault formula. A prediction formula developed in the MDRD study more accurately predicted GFR in AASK patients than these measurements. AASK data were also used to derive a new five-term formula for estimating GFR that was slightly more accurate in the African Americans in the AASK than the MDRD formula (median percentage of error, 12.4% for the MDRD formula versus 12.1% for the AASK formula). Important differences exist in renal variables between African Americans and non-African Americans and between African American men and African American women. Formulas using demographic data and readily measured serum values estimate (125)I-iothalamate GFR.
Adolescent↗
Quantitative shedding of two genotypes of Cryptosporidium parvum in California ground squirrels (Spermophilus beecheyi).
Sixteen percent of California ground squirrels (Spermophilus beecheyi) were found to be shedding an average of 53,875 Cryptosporidium parvum oocysts/g of feces. Male squirrels had a higher prevalence and higher intensity of shedding than did female squirrels. The majority of C. parvum isolates matched a bovine-murine genotype, with a few isolates resembling a porcine genotype. Higher intensities of shedding by males may enhance dissemination and genotypic mixing of this protozoa given males' proclivity to disperse to nonnatal colonies.
Animals↗
Sustained dysfunction of antiviral CD8+ T lymphocytes after infection with hepatitis C virus.
Hepatitis C virus (HCV) sets up persistent infection in the majority of those exposed. It is likely that, as with other persistent viral infections, the efficacy of T-lymphocyte responses influences long-term outcome. However, little is known about the functional capacity of HCV-specific T-lymphocyte responses induced after acute infection. We investigated this by using major histocompatibility complex class I-peptide tetrameric complexes (tetramers), which allow direct detection of specific CD8+ T lymphocytes ex vivo, independently of function. Here we show that, early after infection, virus-specific CD8+ T lymphocytes detected with a panel of four such tetramers are abnormal in terms of their synthesis of antiviral cytokines and lytic activity. Furthermore, this phenotype is commonly maintained long term, since large sustained populations of HCV-specific CD8+ T lymphocytes were identified, which consistently had very poor antiviral cytokine responses as measured in vitro. Overall, HCV-specific CD8+ T lymphocytes show reduced synthesis of tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma) after stimulation with either mitogens or peptides, compared to responses to Epstein-Barr virus and/or cytomegalovirus. This behavior of antiviral CD8+ T lymphocytes induced after HCV infection may contribute to viral persistence through failure to effectively suppress viral replication.
Acute Disease↗
Explaining differences in the severity of familial adenomatous polyposis and the search for modifier genes.
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Adenomatous Polyposis Coli↗
A self-correcting indirect calorimeter system for the measurement of energy balance in small animals.
Indirect calorimetry involves measurement of CO(2) produced and O(2) consumed by an organism. These measurements are then used to calculate energy output, metabolic rate (MR), and respiratory quotient (RQ), a relative assessment of carbohydrate and lipid oxidation. By far the most difficult aspect of indirect calorimetry is measurement of O(2). Moreover, the abundance of O(2) (20.95%) relative to CO(2) (0.03%) in ambient conditions dictates that measurement errors of O(2) have greater implications on calculations of MR and RQ. Because compressed air is not feasible for use with animals in long-term experiments, changes in ambient conditions are nearly unavoidable. A self-correcting indirect calorimetry system was designed and constructed utilizing differential O(2) and CO(2) analyzers and a blank cage to monitor ambient conditions periodically. The system was validated by changing ambient O(2) and CO(2) concentrations by infusing N(2) into the system during a test butane burn. MR and RQ were largely unaffected by these changes in ambient conditions, and inclusion of a blank cage in the system accounted for slight calibration offsets. MR and RQ were measured in mice (n = 95) with and without correction for any small changes in ambient conditions measured in the blank cage. Coefficients of variation for MR and RQ were significantly decreased by taking into account ambient conditions measured in the blank cage (P < 0.001), which resulted in a 2.3% increase in precision for measurement of MR. This system will be used to more accurately assess long-term measurements of energy balance in the many murine models of leanness and obesity to gain better insights into pathophysiology and treatment of human obesity.
Animals↗
The HELLP syndrome: maternal and perinatal outcome.
The HELLP syndrome is a rare condition with a variable presentation, and in general, the outlook for mother and baby is felt to be poor. The aims of this study were to determine the maternal and perinatal outcome in cases of the HELLP syndrome at the Rotunda hospital over a five-year period. A retrospective review of all cases of confirmed HELLP syndrome from 1/1/95 to 1/9/99 was undertaken. Antenatal, intrapartum and neonatal data and in particular, maternal and neonatal complications were recorded. There were 20 cases of HELLP syndrome over the 5-year period. Mean maternal age was 29.8 (19-43) years. 70% were nulliparous. 80% delivered within 24 hours of diagnosis. 85% were delivered by caesarean section. Mean gestation at delivery was 33.5 (24-41) weeks, 65% of which were preterm. 70% of the babies were admitted to the neonatal intensive care unit (NICU). Mean birth weight was 1923g (440-4640g). Mean length of stay was 23.8 (1-68) days. 40% developed respiratory distress syndrome (RDS) with a mean duration of ventilation for these infants of 2.4 (0.5-7) days. There were 2 perinatal deaths both of whom weighed <500g. 95% of women were admitted to the High Dependency Unit. There were no maternal deaths. The mean interval to resolution of laboratory indices to within normal reference ranges was 11 (2-30) days. Maternal morbidity was high, but short-term, with full resolution in all cases. Once the diagnosis was made, delivery was immediate. The neonatal morbidity was also high and was most closely related to the gestation at delivery.
Female↗
The South African National Non-Natural Mortality Surveillance System--rationale, pilot results and evaluation.
BACKGROUND: While individual mortuaries have recorded data for non-natural deaths in time-limited studies, there have been no systematic efforts to draw forensic-medical services and state mortuaries into a nationwide fatal injury surveillance system. Beginning in June 1998, the National Non-Natural Mortality Surveillance System (NMSS) commenced pilot operation. OBJECTIVE: To evaluate the NMSS and illustrate its utility from sample findings. DESIGN: Data entered into the system by mortuary staff were checked against a random sample of cases for which separate forms were completed by an independent researcher. Process observations and follow-up with data users were used to assess the system's acceptability, timeliness and data usefulness. SETTING: Eighteen mortuaries in six provinces representing approximately 35,000 cases per year, or around 50% of all non-natural deaths. PARTICIPANTS: The National Departments of Health; Safety and Security; and Arts, Culture, Science and Technology; national and provincial forensic medico-legal services; the South African Police Services; universities and science research councils. MAIN OUTCOME MEASURES: Surveillance system simplicity, flexibility, acceptability, sensitivity, positive predictive value, representativeness, timeliness, data usefulness and resources. RESULTS: The NMSS was established at 10 target sites. Lack of equipment, personnel resistance, and closure of some mortuaries prevented implementation in the remaining eight mortuaries. Sensitivity was internally assessed and ranged from 65% to 95% for manner of death. Positive predictive value was also internally measured, and ranged from 74% to 80% for manner of death and from 71% to 82% for mechanism of death. Timeliness was good, and basic reports covering most items were available 6 weeks after a case had been examined. While staff found the system simple, acceptability depended on the individuals involved at different mortuaries, and the system was compromised to some extent by bureaucratic barriers. End users found the data to be of great value. NMSS set-up costs totalled approximately R26,000 per mortuary, and it is estimated that maintenance costs will be R8.00 per case registered. CONCLUSIONS: With minimal resources, the NMSS uses existing investigative procedures to describe and report the epidemiology of fatal injuries. The pilot study demonstrates the feasibility of the system, and identifies the need to remove organisational constraints and individual barriers if it is to be sustained and expanded beyond the pilot sites.
Accidents↗
Treatment of swine wastewater in marsh-pond-marsh constructed wetlands.
Swine waste is commonly treated in the USA by flushing into an anaerobic lagoon and subsequently applying to land. This natural system type of application has been part of agricultural practice for many years. However, it is currently under scrutiny by regulators. An alternate natural system technology to treat swine wastewater may be constructed wetland. For this study we used four wetland cells (11 m width x 40 m length) with a marsh-pond-marsh design. The marsh sections were planted to cattail (Typha latifolia, L.) and bulrushes (Scirpus americanus). Two cells were loaded with 16 kg N ha(-1) day(-1) with a detention of 21 days. They removed 51% of the added N. Two additional cells were loaded with 32 kg ha(-1) day(-1) with 10.5 days detention. These cells removed only 37% of the added N. However, treatment operations included cold months in which treatment was much less efficient. Removal of N was moderately correlated with the temperature. During the warmer periods removal efficiencies were more consistent with the high removal rates reported for continuous marsh systems--often > than 70%. Phosphorus removal ranged from 30 to 45%. Aquatic macrophytes (plants and floating) assimilated about 320 and 35 kg ha(-1), respectively of N and P.
Animals↗
Analysis of successful immune responses in persons infected with hepatitis C virus.
Although hepatitis C virus (HCV) infection is very common, identification of patients during acute infection is rare. Consequently, little is known about the immune response during this critical stage of the disease. We analyzed the T lymphocyte response during and after acute resolving HCV infection in three persons, using interferon (IFN)-gamma enzyme-linked immunospot (ELISPOT) and human histocompatibility leukocyte antigen (HLA) peptide tetramer assays. Acute infection was associated with a broadly directed T helper and cytotoxic T lymphocyte (CTL) response, which persisted after resolution of clinical hepatitis and clearance of viremia. At the earliest time point studied, highly activated CTL populations were observed that temporarily failed to secrete IFN-gamma, a "stunned" phenotype, from which they recovered as viremia declined. In long-term HCV-seropositive persons, CTL responses were more common in persons who had cleared viremia compared with those with persistent viremia, although the frequencies of HCV-specific CTLs were lower than those found in persons during and after resolution of acute HCV infection. These studies demonstrate a strong and persistent CTL response in resolving acute HCV infection, and provide rationale to explore immune augmentation as a therapeutic intervention in chronic HCV infection.
Acute Disease↗
Mesoscopic analysis of structure and strength of dislocation junctions in fcc metals
We develop a finite-element-based nodal dislocation dynamics model to simulate the structure and strength of dislocation junctions in fcc crystals. The model is based on anisotropic elasticity theory supplemented by the explicit inclusion of the separation of perfect dislocations into partial dislocations bounding a stacking fault. We demonstrate that the model reproduces in precise detail the structure of the Lomer-Cottrell lock already obtained from atomistic simulations. In light of this success, we also examine the strength of junctions culminating in a stress-strength diagram which is the locus of points in stress space corresponding to dissolution of the junction.
Journal Article↗
CD8+ T lymphocyte responses are induced during acute hepatitis C virus infection but are not sustained.
Cellular immune responses are likely to play a key role in determining the clinical outcome in acute infection with hepatitis C virus (HCV), but the dynamics of such responses and their relationship to viral clearance are poorly understood. In a previous study we have shown highly activated, multispecific cytotoxic T lymphocyte responses arising early and persisting in an individual who subsequently cleared the virus. In this study the HCV-specific CD8+ lymphocytes response has been similarly analyzed, using peptide-HLA class I tetramers, in a further nine individuals with documented acute HCV infection, six of whom failed to clear the virus. Significant populations of virus-specific CD8+ lymphocytes were detected at the peak of acute hepatic illness (maximally 3.5% of CD8+ lymphocytes). Frequencies were commonly lower than those seen previously and were generally not sustained. Early HCV-specific CD8+ lymphocytes showed an activated phenotype in all patients (CD38+ and HLA class II+), but this activation was short-lived. Failure to sustain sufficient numbers of activated virus-specific CD8+ lymphocytes may contribute to persistence of HCV.
Acute Disease↗
Treatment of HIV-associated invasive anal cancer with combined chemoradiation.
There is an increased frequency of invasive anal cancer in HIV-seropositive men. Early treatment strategies in this patient group employed reduced dosages of chemotherapy or radiotherapy alone to reduce toxicity. Since 1989 we have used combined modality treatment consisting of chemotherapy 5-fluorouracil (5-FU) and mitomycin C, and concomitant radical radiotherapy to the pelvis (38-51 Gy in 20-30 fractions), with most patients receiving a perineal boost (10-18 Gy). 12 homosexual HIV-positive men have been treated. The median CD4 count at diagnosis of anal cancer was 209 cells/microl (range: 29-380 cells/microl), 5 had prior AIDS defining diagnoses. No patients had metastatic disease. Complete remissions were obtained in 9/11 evaluable patients and in 1 further patient following surgery. 2 patients relapsed both within 6 months of diagnosis. At a median follow-up of 4.8 years (range: 0.4-10 years), 4 patients have died (2 from anal cancer, 1 from treatment-related consequences and 1 from opportunistic infection in remission). Actuarial 2-year survival is 60% (95% confidence interval (CI): 29-91%). Grade 3 haematological toxicity was recorded in 3 patients, grade 4 and 5 gastrointestinal toxicity in 1 patient each and grade 3 skin toxicity in 1 patient. Radical chemoradiation may be given safely at conventional doses in HIV-positive patients, with a high complete response rate.
Adult↗
Image analysis for computer-assisted internal fixation of hip fractures.
This paper focuses on the task of automatic feature detection for intra-operative drilling trajectory planning for computer-assisted internal fixation of hip fractures. The features of interest are the lateral cortex line of the femoral shaft, the femoral neck centre and the femoral head centre, the latter being the most challenging of all. Since the object is known, the detection process is regarded as a localisation task rather than a recognition one. Simple anatomical relationships between bone parts provide a naturally hierarchical approach to searching, allowing refinement of image-derived information based on a priori constraints. Use of knowledge and an unconventional "divide-and-conquer" approach produce more reliable and faster results than the standard global image processing routine. Analysis of summed 1D grey level profiles is used as a main segmentation tool to carry out the above strategy.
Artificial Intelligence↗
Stochastically simulated assessment of anabolic treatment following varying degrees of cancellous bone resorption.
The aim of this study was to investigate the recovery in cancellous bone stiffness resulting from anabolic treatment following varying degrees of resorption, using a stochastic simulation applied to a simplistic structure consisting of five vertical and five horizontal trabeculae. The structure was initially resorbed, and "bone" elements were stochastically removed until nominal resorptions of 10%, 15%, 20%, 25%, and 30% were achieved. A stochastic simulation of anabolic treatment was then applied where bone elements were added, continuing until the original stiffness had been regained, for example, simulating treatment of a patient with an anabolic agent after a period of postmenopausal resorption. The resorption and anabolic simulations were repeated three times for each of the nominal resorptions. The stiffness of the bone structure decreased linearly with resorption, with a slope of approximately -2 and an R(2) of 97.0%; hence, the stiffness fell at approximately twice the rate of the reduction in density. When the various structures regained their original density, the resultant stiffness also had a linear relationship with the original resorption, with a slope of -1 and a lower R(2) of 86.1%. This implies that the reduction in stiffness, when original density was regained, fell proportionately with the degree of initial resorption and, therefore, after a resorption of 30%, when original density was regained, the stiffness of the resultant structure was approximately 30% less than that of the original structure. The density required for the original stiffness to be regained increased linearly with the degree of initial resorption, with a slope of approximately 0.5 and an R(2) of 65.2%, lower than that observed for the previous relationships. This indicates a greater spread of data and suggests greater variability in the formation phase beyond the point of regained original density. Because irreversible connectivity reduction is widely considered to be one of the earliest manifestations of estrogen loss, these findings, although obtained on a simulation of a simplistic cancellous bone structure, support the concept of early intervention to prevent potentially irreversible deterioration of trabecular architecture after menopause.
Bone Resorption↗
Irritant contact dermatitis secondary to fiberglass: an unusual presentation.
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Adult↗