Biomedical subjects

Patricia Price

Publications and source records attributed to Patricia Price.

At least 19 recordsLinked to original sources

PubMed2006

Cell surface markers of regulatory T cells are not associated with increased forkhead box p3 expression in blood CD4+ T cells from HIV-infected patients responding to antiretroviral therapy.

Regulatory T (Treg) cells may attenuate host immune responses to pathogens, including HIV and opportunistic pathogens in HIV-infected patients. Treated and untreated progressive HIV disease represent a range of immunological scenarios with potentially different roles for Treg cells. A cell surface marker to determine Treg cell numbers would assist in identifying situations where Treg cells are important. Here we show that levels of Foxp3 mRNA are increased in CD4+ T cells from HIV-infected patients responding to antiretroviral therapy. However, the proportion of peripheral blood CD4+ and CD8+ T cells expressing CD25, neuropilin-1, glucocorticoid-induced TNF receptor and lymphocyte activation gene-3 did not differ as a result of treated or untreated HIV infection when compared with HIV-seronegative controls. Hence, none of the putative Treg cell surface markers identified T-cell populations in peripheral blood that mirrored the effects of HIV infection and antiretroviral therapy on Foxp3 expression.

Anti-Retroviral Agents↗

PubMed2006

Familial inclusion body myositis in a mother and son with different ancestral MHC haplotypes.

An Ashkenazi Jewish family in which the mother and a son both have inclusion body myositis (IBM) is reported. The condition developed at an earlier age and was more rapidly progressive and less responsive to treatment in the son than in the mother or other IBM patients in our clinic. Genetic analysis showed that the mother carried alleles of the 8.1 MHC ancestral haplotype (AH; HLA-B8, DRB1*0301), which is found in 85% of IBM patients in Western Australia. The son did not inherit this haplotype, but carried alleles characteristic of the 52.1AH (HLA-B5, DRB1*1502) of paternal origin. The findings indicate that in this family either the 8.1AH or 52.1AH may carry susceptibility for IBM and that the 52.1AH is associated with a more severe and treatment-resistant form of the disease.

Alleles↗

PubMed2006

The influence of diabetes and lower limb arterial disease on cutaneous foot perfusion.

OBJECTIVE: Peripheral arterial occlusive disease and peripheral neuropathy are major risk factors in diabetic foot disease. We evaluated the relative influences of noncritical lower limb arterial disease and peripheral neuropathy on cutaneous foot perfusion in diabetes. METHOD: Toe-brachial pressure indices, transcutaneous oxygen, and carbon dioxide tensions at foot and chest sites were measured in individuals with diabetes, with or without detectable peripheral neuropathy and with or without significant arterial disease on color duplex imaging. Subjects without diabetes, with and without arterial disease, were used as controls. RESULTS: A total of 130 limbs were studied during an 8-month period. Toe-brachial pressure indices reflected the presence of arterial disease in all groups. Foot transcutaneous oxygen values were reduced in diabetes and correlated with chest transcutaneous oxygen values. Low foot transcutaneous oxygen with elevated transcutaneous carbon dioxide values were only demonstrated in individuals with diabetes, arterial disease, and peripheral neuropathy. Toe-brachial pressure indices demonstrated a positive correlation with foot transcutaneous oxygen values, but values >1.2 demonstrated a negative correlation. CONCLUSIONS: We demonstrated two influences on cutaneous foot perfusion in diabetes: (1) a global microcirculatory dysfunction, reflected in low chest and foot transcutaneous oxygen values, and (2) macrovascular disease as indicated by reduced toe-brachial pressure indices and foot transcutaneous oxygen values. Further, the results demonstrated that in diabetic individuals without critical limb ischemia, impaired foot perfusion secondary to arterial disease is amplified significantly by coexisting microcirculatory disease.

Aged↗

PubMed2006

A T2 cytokine environment may not limit T1 responses in human immunodeficiency virus patients with a favourable response to antiretroviral therapy.

Low-level production of interferon-gamma (IFN-gamma) marks human immunodeficiency virus (HIV)-induced immunodeficiency and has been ascribed to a bias towards T2 cytokines. This was investigated in two cross-sectional studies of HIV patients who were immunodeficient when they began antiretroviral therapy (ART) and had stable increases in CD4 T-cell counts. Blood leucocytes were assessed unstimulated or after stimulation with cytomegalovirus (CMV), anti-CD3 or mitogen. IFN-gamma and interleukin (IL)-5 responses were initially assessed by enzyme-linked immunosorbent spot-forming cell assay (ELISPOT) and enzyme-linked immunosorbent assay (ELISA). We then adopted a sensitive reverse transcription-polymerase chain reaction (RT-PCR) system to assess IFN-gamma, IL-5, IL-4 and IL-4delta2 (an inhibitory splice variant of IL-4) mRNA. The results were correlated with putative serological markers of a T1 [lymphocyte activation gene-3 (LAG-3), CD26] or a T2 [CD30, immunoglobulin E (IgE)] cytokine environment. IL-5 production and IgE levels were elevated in patients. IgE levels did not correlate with IFN-gamma, but showed an inverse correlation with IL-5 released in culture (P = 0.05). The levels of IL-4, IFN-gamma, IL-5 and IL-4delta2 mRNA were correlated after anti-CD3 stimulation, where IL-5 was the best predictor of IFN-gamma mRNA (P = 0.006). Weak positive correlations were evident between CD30 and cytokine mRNA levels, whilst IgE correlated inversely with IL-4, IL-4delta2, IL-5 and IFN-gamma mRNA levels. These analyses provide no evidence for an inverse relationship between T1 and T2 cytokine responses in HIV patients, but suggest that the elevation of IgE marks low cytokine responses.

Adult↗

PubMed2006

Low CD4+ T-cell counts in HIV patients receiving effective antiretroviral therapy are associated with CD4+ T-cell activation and senescence but not with lower effector memory T-cell function.

The adverse effects of immune activation on CD4(+) T-cell recovery and the relationship between CD4(+) T-cell counts and effector T-cell function were examined in HIV-1 patients receiving long-term effective ART. Patients with nadir CD4(+) T-cell counts <100/microl, > 12 months on ART and >6 months with <50 HIV RNA copies/ml were stratified by current CD4(+) T-cell counts and patients from the lowest (n = 15) and highest (n = 12) tertiles were studied. We assessed proliferation (Ki67), activation (HLA-DR, CD38) and replicative senescence (CD57) by flow cytometry and CD4(+) T-cell responses to CMV by IFN-gamma ELISpot. Proportions of CD4(+) T-cells expressing HLA-DR or CD57 were strong univariate predictors of total (P = 0.0002 and P = 0.002) and naive (P < 0.0001 and P < 0.0001, respectively) CD4(+) T-cell counts, suggesting that CD4(+) T-cell activation drives the depletion of naive CD4(+) T-cells. This was clearest in patients with a small/undetectable thymus. IFN-gamma responses to CMV were similar in patients with low or high CD4(+) T-cell counts.

Adult↗

PubMed2006

Elevation of radiolabelled thymidine uptake in RIF-1 fibrosarcoma and HT29 colon adenocarcinoma cells after treatment with thymidylate synthase inhibitors.

PURPOSE: We recently showed an increase in tumour uptake of 2-[(11)C]thymidine in patients with gastrointestinal malignancies after thymidylate synthase (TS) inhibition. To understand the phenomenon in more detail, we investigated whether TS inhibition by different TS inhibitors leads to a dose- and time-dependent change in the uptake of radiolabelled thymidine, and whether radiotracer uptake is related to changes in cell viability resulting from treatment. METHODS: RIF-1 and HT29 cells were treated with the TS inhibitors 5-fluorouracil (5-FU) and AG337 (nolatrexed dihydrochloride), as well as cisplatin as control. The cell viability and net accumulation of [(3)H]thymidine after a 1-h pulse was determined at different times after drug treatment. RESULTS: In both cell lines, [(3)H]thymidine uptake increased after a 2-h treatment with 5-FU, in a dose- and time-dependent manner. [(3)H]thymidine uptake decreased at 24 and 48 h post treatment. AG337 also produced a similar effect. In contrast to the TS inhibitors, cisplatin decreased [(3)H]thymidine uptake in RIF-1 and HT29 cells at all time points. Cell viability was compromised only after 24 h. CONCLUSION: Using two types of TS inhibitor, we have shown an increase in [(3)H]thymidine uptake, in a dose-dependent manner, a few hours after TS inhibition when the cell viability was not compromised. This effect was not seen with a non-TS inhibitor. These findings suggest that 2-[(11)C]thymidine positron emission tomography can be used to study TS inhibition in vivo at early time points when cell viability is not compromised and may therefore be helpful in the development of new TS inhibitors and in differentiating between patients with tumours sensitive to TS inhibitors and those unlikely to respond.

Adenocarcinoma↗

PubMed2006

Interferon-gamma responses to Candida recover slowly or remain low in immunodeficient HIV patients responding to ART.

Extended assessments of memory T-cell responses in HIV patients who have a satisfactory virological response to combination antiretroviral therapy (CART) have been limited by availability of longitudinal samples and of antigens to which most individuals (including HIV-negative controls) have been exposed. Studies of cytomegalovirus (CMV) show that interferon-gamma (IFN-gamma) responses never recover completely, but this may be antigen-specific. Here we present responses to Candida and CMV antigens analyzed using a statistical approach that derives overall trends from samples collected at variable time points. Results were considered in relation to putative markers of T-regulatory cells. Blood mononuclear cells collected from seventeen HIV-1 patients (nadir <100 CD4 T cells/mL) 0-8 years after initiation of CART were stimulated with Candida spp lysate, Candida enolase protein or CMV lysate and production of IFN-gamma was assessed by ELISpot assay. CD4 T-cell counts increased fivefold and stabilized within 24 months on CART, following control of plasma viremia. IFN-gamma responses to Candida antigens began low and increased slowly, generating positive slope up to 60 months on CART (Candida enolase p=0.008; Candida lysate p=0.03; mixed-model Wald test). Only two patients displayed a CMV or Candida-specific IFN-gamma response above the median for seronegative controls. Proportions of T cells expressing CD25 or CD57 did not correlate with IFN-gamma responses. Slow reconstitution of IFN-gamma responses to CMV and Candida in previously immunodeficient patients with restored CD4+ T-cell counts on CART suggests a broad and nonresolving defect in memory T-cell responses.

Adult↗

PubMed2006

Recovery of CD4+ T Cells in HIV patients with a stable virologic response to antiretroviral therapy is associated with polymorphisms of interleukin-6 and central major histocompatibility complex genes.

We investigated whether polymorphisms in genes associated with HIV disease progression and/or immune activation affect CD4+ T-cell recovery in HIV patients who began combination antiretroviral therapy (ART) with advanced immunodeficiency and achieved stable control of plasma viremia. Patients with CD4 T-cell counts <300 cells/microL (n = 33) and >400 cells/microL (n = 37) on ART were compared. A multiple case-control logistic regression associated carriage of BAT1(1,2) or interleukin (IL)6-174(2,2) with low CD4 T-cell counts (P = 0.012). BAT1*2 uniquely marks the central major histocompatibility complex region of a conserved haplotype (HLA-A1,B8,BAT1*2,TNFA-308*2,DR3,DQ2). There was no association between alleles carried at CCR5Delta32, CCR5 59029, CCR5 59353, CCR2+190 (V64I), SDF1 3'UTR, IL1A+4845, IL1B+3953, IL4-589, IL10-592, IL10-R1+536, IL10-R1+1112, IL12B 3'UTR, TNFA-308, or TNFA-1031 and CD4 T-cell counts. We suggest that immune activation and/or CD4 T-cell apoptosis in HIV patients on effective ART is influenced by genetic factors.

Adult↗

PubMed2006

Thymic function in severely immunodeficient HIV type 1-infected patients receiving stable and effective antiretroviral therapy.

The role of the thymus in long-term immune reconstitution has not been addressed in HIV patients who were severely immunodeficient prior to successful treatment with combination antiretroviral therapy (ART). Adult HIV-1 patients (n = 78) with nadir CD4+ T cell counts <100 T cells/microl, at least 12 months on ART and 6 months of complete viral suppression (<50 HIV RNA copies/ml) were selected from a patient database. The cohort was divided according to current CD4+ T cell counts and patients from the lowest (n = 15) and highest (n = 12) tertiles were studied. Thymic volume was assessed by spiral computed tomography. Naive (CD45RA+CD62L+) and replicating (Ki67+) T cells were quantitated by flow cytometry, T cell receptor excision circles (TREC) were assessed by real-time PCR, and serum IL-7 and testosterone by immunoassay. Patients with low CD4+ T cell counts had smaller thymuses [0(0-5.3) vs. 3.5(0-15.6) cm(3), p = 0.04] and were more likely to have no detectable thymus. They had similar proportions of replicating cells, but fewer naive CD4+ and CD8+ T cells and less TREC in CD4+ and CD8+ T cells/ml of blood than patients with high CD4+ T cell counts. However, some patients with no detectable thymus had high numbers of naive and TREC-bearing T cells. Thus, the recovery of CD4+ T cells in severely immunodeficient HIV patients with a virological response to ART is probably limited by thymic function. However, the data are consistent with extrathymic T cell production contributing to the naive T cell pool in some patients.

Adult↗

PubMed2006

CXCR4 or CCR5 tropism of human immunodeficiency virus type 1 isolates does not determine the immunological milieu in patients responding to antiretroviral therapy.

Here we address whether CCR5 or CXCR4 tropism of the predominant viral strain detected before or on combination antiretroviral therapy (ART) explains why some human immunodeficiency virus (HIV)-infected patients who begin ART with advanced HIV disease retain low interferon (IFN)-gamma responses, despite recovery of CD4(+) T cell counts. Tropism was determined by culture and confirmed by gp120 V3 loop sequence of multiple plasma samples in eight adult male patients who began treatment with <50 CD4(+) T cells/microL. Four patients had mixed infections, one had only R5 HIV, and three had only X4 HIV. Of these, two carried CCR5Delta32. Viral tropism was not related to CD4(+) T cell counts or HIV RNA levels. When immunological responses were monitored over several years, IFN-gamma responses to cytomegalovirus were below the median value of uninfected controls and similar in patients with R5, X4, or mixed infection. Interleukin-5 responses were low and plasma soluble CD30 levels were high at treatment onset, but resolved with control of HIV replication irrespective of HIV tropism. Levels of LAG-3 (lymphocyte activation gene-3 protein) were elevated in patients with uncontrolled HIV replication. Hence the immunological milieu did not reflect HIV tropism.

Adult↗

PubMed2006

Hepatitis C virus genotype and HIV coinfection affect cytokine mRNA levels in unstimulated PBMC but do not shift the T1/T2 balance.

Rapid progression of hepatitis C virus (HCV) disease in patients with HIV/HCV may reflect different cytokine responses and be influenced by HCV genotype. This is addressed by a study of patients with HIV/HCV coinfection and infection with HCV genotype 2 or 3 (2/3). They are compared with coinfected patients infected with genotype 1 and HCV monoinfected patients matched for HCV genotype. IFN-gamma, IL-10, IL-4 and IL-4delta2 mRNA were quantified by real-time PCR in unstimulated PBMC and after in vitro stimulation with HCV core or nonstructural 3/4A antigen. In unstimulated PBMC, levels of IFN-gamma and IL-4 mRNA were lowest in HIV/HCV genotype 1 patients, intermediate in HIV/HCV genotype 2/3 patients and highest in HCV genotype 2/3 patients. Neither HCV genotype nor HIV affected levels of IL-10 mRNA in unstimulated PBMC or IFN-gamma, IL-4 and IL-10 mRNA in PBMC stimulated with HCV antigens. Levels of IL-4 and IL-4delta2 mRNA correlated in mitogen-stimulated PBMC from all patient groups but both were low in HIV/HCV genotype 1 patients. Serum soluble CD30 levels (a putative marker of a T2 cytokine environment) did not differ between patient groups. The data do not suggest a shift in the T1/T2 balance driven by HIV coinfection or HCV genotype but either may affect IL-4 bioavailability.

Adult↗

PubMed2006

Tumour necrosis factor: implications for surgical patients.

Tumour necrosis factor alpha (TNF-alpha) is an inflammatory cytokine primarily produced by macrophages. It is a unique protein with contradictive properties; it has the ability to induce cellular death by apoptosis and oncosis, but can also induce cellular regeneration and growth. Genetic polymorphisms in TNFA have been associated with poor outcome in some surgical patients and this may provide a useful tool to screen for high-risk patients. Manipulating TNF-alpha levels in vivo may influence the progression of several pathological conditions. TNF-alpha has anti-cancer properties and has been used to treat cancer patients. Treatment with anti-TNF-alpha drugs and antibodies has been successful in rheumatoid arthritis and other autoimmune diseases, but disappointing in the management of patients with sepsis. This review article focuses on the biological activities, genetic polymorphism of TNFA and the role of TNF-alpha and anti-TNF-alpha treatments, based on animal experiments and clinical trials.

Animals↗

PubMed2006

The management of deep sternal wound infections using vacuum assisted closure (V.A.C.) therapy.

A group of international experts met in May 2006 to develop clinical guidelines on the practical application of vacuum assisted closure (V.A.C.)+ therapy in deep sternal wound infections. Group discussion and an anonymous interactive voting system were used to develop content. The recommendations are based on current evidence or, where this was not available, the majority consensus of the international group. The principles of treatment for deep sternal wound infections include early recognition and treatment of infection. V.A.C. therapy should be instigated early, following thorough wound irrigation and surgical debridement. V.A.C. therapy in deep sternal wound infections requires specialist surgical supervision and should only be undertaken by clinicians with adequate experience and training in the use of the technique.

Humans↗

PubMed2006

Genetic and functional analysis of R5X4 human immunodeficiency virus type 1 envelope glycoproteins derived from two individuals homozygous for the CCR5delta32 allele.

We characterized human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Env) isolated from two HIV-1-infected CCR5delta32 homozygotes. Envs from both subjects used CCR5 and CXCR4 for entry into transfected cells. Most R5X4 Envs were lymphocyte-tropic and used CXCR4 exclusively for entry into peripheral blood mononuclear cells (PBMC), but a subset was dually lymphocyte- and macrophage-tropic and used either CCR5 or CXCR4 for entry into PBMC and monocyte-derived macrophages. The persistence of CCR5-using HIV-1 in two CCR5delta32 homozygotes suggests the conserved CCR5 binding domain of Env is highly stable and provides new mechanistic insights important for HIV-1 transmission and persistence.

Alleles↗

PubMed2005

Anxiety and self-consciousness in patients with facial lacerations one week and six months later.

We explored the psychological impact of disfigurement resulting from facial lacerations in patients who presented at an accident and emergency department in the UK. Patients participated in relevant sections of the Derriford Appearance Scale and State Trait Anxiety Inventory at one week and six months after injury. In all patients self-consciousness and anxiety scores were higher than in the general population. The extent of the scar, the patient's living arrangements, and the cause of the injury were significantly related to self-consciousness and anxiety. General self-consciousness improved at six months but not social self-consciousness and anxiety. These injuries may have a considerable impact on the lives of the affected people.

Accidents↗

PubMed2005

Risk of plantar ulceration in diabetic patients with single-leg amputation.

BACKGROUND: There is a disconcerting rate of bilateral limb loss in patients with diabetes. Therefore, this study aimed to explore plantar loading of the surviving foot following unilateral trans-tibial amputation within a wider context of daily walking activity to investigate the precise risk to the surviving limb. METHODS: Twenty-one subjects with diabetic neuropathy and trans-tibial amputation were matched for weight; height; age and gender with 21 control subjects with diabetic neuropathy without history of plantar ulceration. Gait parameters, in-shoe plantar pressure distribution and daily walking (using the step activity monitor) were recorded. Student's t-tests were used to compare groups (alpha-level: 0.05). FINDINGS: The trans-tibial amputations group walked almost 30% slower compared to controls (P < 0.01), with reduced cadence (P < 0.01), and shorter strides (P < 0.01). Despite walking slower, the surviving foot showed higher mean peak plantar pressures in the trans-tibial amputations group over the heel (P < 0.001) however there was no significant difference over the I-II and lateral III-IV-V metatarso-phalangeal regions. Pressure time integral was higher over the heel (P < 0.00), I-II (P < 0.01) and III-IV-V metatarso-phalangeal (P < 0.05) in the trans-tibial amputations group. The amputee group walked less steps per day (P < 0.01). INTERPRETATION: Adaptations in gait and level of walking activity affect plantar pressure distribution and ultimately the risk of ulceration to the surviving foot. Therefore rehabilitation measures should consider implications for plantar loading and the potential risk of ulceration to the surviving foot.

Adult↗

PubMed2005

HIV patients on antiretroviral therapy have high frequencies of CD8 T cells specific for Immediate Early protein-1 of cytomegalovirus.

OBJECTIVE: To assess the frequency and phenotype of cytomegalovirus (CMV)-specific CD8 T cells in previously immunocompromised HIV patients with stable undetectable HIV viremia due to highly active antiretroviral therapy (HAART). METHODS: Twenty-one CMV-seropositive HIV patients with nadir CD4 T-cell counts < 50 x 10(6) cells/l, at least 4 years on HAART and 6 months of complete viral suppression (< 50 HIV RNA copies/ml) and 12 CMV-seropositive, HIV-seronegative age/sex-matched controls were studied. CD4 and CD8 T-cell responses to whole CMV and two HLA-A*02 restricted CMV peptides [NLV from pp65 and VLE from Immediate Early 1 (IE1)] were measured by interferon (IFN)gamma ELISpot. Phenotypes of peptide-specific CD8 T cells were determined by tetramer staining. RESULTS: In the ELISpot assay, HIV patients had significantly more CD8 T cells producing IFN gamma in response to VLE than controls, whereas numbers of NLV-specific and CMV-specific IFN gamma spots were similar. Four HIV patients and one control had large VLE and/or NLV-specific CD8 T-cell populations despite the absence of CMV-specific CD4 T cells. The majority of peptide-specific CD8 T cells from HIV patients and controls were CD28-, CD45RO+ and CD45RA-. However, a significantly higher proportion of VLE-specific CD8 T cells expressed perforin compared to NLV-specific CD8 T cells in HIV patients. CONCLUSIONS: HIV patients had elevated numbers of IE1-specific, IFNgamma-producing perforin-positive CD8 T cells compared to controls. As IE1 is expressed early during CMV reactivation, these cells may be important for preventing CMV replication to pathogenic levels. In addition, CMV-specific CD4 T cells are not essential for maintenance of large populations of CMV-specific CD8 T cells in aviremic HIV patients on HAART.

Adult↗

PubMed2005

Psychological distress, comorbidities, and health behaviors among U.S. adults with seizures: results from the 2002 National Health Interview Survey.

PURPOSE: To examine the association of seizures with health-related quality of life (HRQOL), physical and psychiatric comorbidities, and health behaviors. METHODS: We analyzed data obtained from adults aged 18 years or older (n = 30,445) who participated in the 2002 National Health Interview Survey, an ongoing, computer-assisted personal interview of the noninstitutionalized U.S. population. RESULTS: An estimated 1.4% of adults 18 years or older reported being told by a health care professional that they had seizures. Persons with seizures were significantly more likely than those without seizures to report lower levels of education, higher levels of unemployment, pain, hypersomnia and insomnia, and psychological distress (e.g., feelings of sadness, nervousness, hopelessness, and worthlessness). In addition, they were significantly more likely to report insufficient leisure-time physical activity as well as physical comorbidities such as cancer, arthritis, heart disease, stroke, asthma, severe headaches, lower back pain, and neck pain. CONCLUSIONS: Our findings suggest that it is advisable for health care professionals to assess psychiatric and physical comorbidities among patients with a history of seizures potentially to improve patient health outcomes. Furthermore, public health surveillance systems should include questions on seizures, epilepsy, and mental health to better examine associations among these disorders and to better identify populations meriting further assessment and intervention.

Adolescent↗