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Biomedical subjects

L Harper

Publications and source records attributed to L Harper.

At least 37 records · Page 2Linked to original sources
PubMed2004

Propylthiouracil and carbimazole associated-antineutrophil cytoplasmic antibodies (ANCA) in patients with Graves' disease.

OBJECTIVE: Propylthiouracil treatment of Graves' disease has been postulated to provoke antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We aimed to investigate whether carbimazole therapy was also associated with increased risk of ANCA. DESIGN: The occurrence of ANCA and the relationship to thionamide treatment was investigated in a cross-sectional study in a consecutive series of 407 patients' with Graves' disease, 200 with Hashimoto's thyroiditis and 649 normal euthyroid subjects. MEASUREMENTS: ANCA was measured by indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA) for proteinase 3 and myeloperoxidase-ANCA. RESULTS: The prevalence of ANCA, as measured by IIF, was increased in the Graves' disease cohort (19.9%) compared with euthyroid controls (4.6%; P < 0.001). The prevalence of MPO-ANCA (measured by ELISA) was also increased in Graves' disease (P = 0.019). ANCA prevalence was more strongly associated with propylthiouracil treatment than carbimazole (P = 0.0265), although risk of ANCA was also higher in Graves' patients treated with carbimazole than controls (RR 2.2, P < 0.0001). ANCA positivity was not increased in patients with Hashimoto's thyroiditis. CONCLUSION: This study revealed a high prevalence of ANCA in treated patients with Graves' disease but not in those with Hashimoto's thyroiditis. Furthermore, within the Graves' disease population, ANCA development was associated with propylthiouracil usage to a greater extent than carbimazole. These findings suggest that the altered immune environment associated with autoimmune thyroid disease is not sufficient to develop ANCA but treatment with thionamides is important in promoting ANCA development.

Adult↗
PubMed2003

Cold legs: a potential indicator of negative outcome in the rehabilitation of patients with patellofemoral pain syndrome.

PURPOSE: The purpose of this paper is to explore the link between a poor outcome in response to an exercise based approach to physiotherapy, in patients with patellofemoral dysfunction and a self-report of legs feeling cold even in warm surroundings. SCOPE: The study was carried out in the physiotherapy outpatients department of Burnley General Hospital, Lancashire, UK with 87 consecutively referred patients with a diagnosis of patellofemoral pain syndrome being assessed for suitability for entry into the study. Of these 77 entered the study with 14 (18%), of these responding 'Yes' to the question 'Do your legs feel cold even in warm surroundings?' All patients were assessed using four outcome measures prior to the commencement of a standardised rehabilitation programme consisting of lower limb biarticular muscle stretching, vastus medialis training and patella taping or biofeedback. The patients were reassessed using the same outcome measures 3 months after completing their course of treatment. CONCLUSIONS: Patients who responded 'Yes' to the question 'Do your legs feel cold even in warm surroundings?' reported higher pain levels and tolerated less physical activity than non-cold sufferers at initial assessment, these differences were statistically significant. The cold sufferers showed less improvement on all of the outcome measures although the differences between the two groups only reached statistical significance for one of the outcome measures. The implications of this in relation to clinical practice are discussed.

Adolescent↗
PubMed2003

Interest of laparoscopy in polysplenia syndrome.

Polysplenia syndrome (PS) is usually discovered in symptomatic patients in association with congenital heart disease or biliary atresia. Asymptomatic patients can present associated anomalies of the digestive tract such as intestinal malrotation and gastric or splenic malfixation. We report a case of PS presenting as a left flank mass shown to be an accessory spleen by denatured red blood cell scintigraphy. Upper gastrointestinal tract studies showed intestinal malrotation. Laparoscopic exploration confirmed intestinal malrotation and showed the absence of fixation of the accessory spleen. We performed a laparoscopic Ladd's procedure followed by fixation of the accessory spleen and resection of Meckel's diverticulum through a short left-flank incision.

Child↗
PubMed2003

There is differential loss of pyramidal cells from the human hippocampus with survival after blunt head injury.

The experimental literature has shown that neurons within sub-fields of the hippocampus possess differential sensitivities to cell loss after different types of insult to the brain. In humans, after blunt head injury, differential neuronal responses between sub-fields of the hippocampus up to 72 hours after injury have been documented. But, in only a small part of the literature have data for alterations in real numbers of neurons been provided. In this study the hypothesis was tested that, after severe blunt head injury in humans, the total number of neurons within a defined volume of brain tissue differed between different sub-fields of the hippocampus and between groups of patients with differing post-traumatic survivals. Stereological methods were used to measure total cross-sectional area of sub-fields of the hippocampus taken at the level of the lateral geniculate nucleus and count numbers of neurons within each of the CA1, CA2, CA3, and CA4 sub-fields of the hippocampus in patients. The patients used in this study were categorized as follows: Group 1 (early) had survived for 1 week or less; Group 2 (late) survived 6 months or longer after fatal severe head injury; and Group 3 (controls) consisted of age-matched patients that had no history of head injury or disease prior to death. There was a significant loss in cross-sectional area in sub-fields CA3 and CA4 at 1 week or less after injury and in sub-field CA1 at 6 months and greater survival. There was no change in CA2. There was loss of neurons from within a predefined volume of brain tissue in sub-fields CA1, CA3, and CA4 one week or less after injury. But there was no loss in CA2. There was continued loss of neurons from sub-fields CA1 and CA4 between 1 week and 6 months and greater survival, but there was no loss of neurons in sub-fields CA2 and CA3 within the same period. These novel data show that after human severe head injury there is first an acute loss (1 week or less survival) of pyramidal neurons in all hippocampal sub-fields except CA2. Second, there is an ongoing loss of neurons in sub-field CA1 and, most notably, in sub-field CA4, in patients surviving for more than 6 months. However, in neither group of patients is there loss of neurons from sub-field CA2.

Adolescent↗
PubMed2002

Hypogalactosylation of serum IgG in patients with ANCA-associated systemic vasculitis.

The triad of small vessel vasculitides (SVV) comprise Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CS). All three are associated with presence of circulating IgG antineutrophil cytoplasm antibodies (ANCA) which target autoantigens contained, primarily, within neutrophil azurophilic granules. The widely accepted model of pathogenesis suggests that ANCA activate cytokine-primed neutrophils within the microvasculature, leading to by-stander damage to endothelial cells, and rapid escalation of inflammation with recruitment of mononuclear cells. Activation may be initiated, in vitro, by the coligation of the PR3 or MPO antigen, translocated to the cell surface, and FcgammaRIIa/FcgammaRIIIb receptors. This suggests that the IgG subclass profile of ANCA and, possibly, its glycosylation status could influence the inflammatory mechanisms activated. The glycosylation status of total IgG isolated from the sera of patients with WG (13), MPA (6) and CSS (1) was determined by analysis of the released oligosaccharides. A deficit in IgG galactosylation is demonstrated for all patient samples, compared to controls. The mean percentage values for the agalactosylated (G0) oligosaccharides were 57% (SD +/- 9.71), 47% (SD +/- 4.25) and 28% (SD +/- 4.09) for WG, MPO and control samples, respectively. The G0 levels for polyclonal IgG isolated from the sera of both WG and MPA patients were significantly increased compared to controls (P < 0.0001). The major glycoform present therefore is agalactosylated (G0) IgG. In previous studies the G0 glycoform of IgG has been shown to bind and activate mannan binding lectin, and hence to activate the complement cascade, and to facilitate mannose receptor binding and the uptake of IgG complexes by macrophages and dendritic cells. Both of these activities could impact on the processing and presentation of self-antigens in autoimmune disease.

Adolescent↗
PubMed2002

Adjuvant treatment of patients with antineutrophil cytoplasmic antibody-associated vasculitis with vitamins E and C reduces superoxide production by neutrophils.

OBJECTIVES: Neutrophils when activated generate a respiratory burst which has been implicated in the pathogenesis of primary systemic vasculitis. Neutrophils from patients with vasculitis have a greater respiratory burst than normal healthy donors. The aim of this study was to assess the effects of antioxidant treatment (vitamins E and C) on the generation of a respiratory burst from neutrophils isolated from patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS: Neutrophils were isolated from patients with systemic vasculitis and healthy donors. Spontaneous superoxide generation was measured by the reduction of ferricytochrome c. The patients were treated with antioxidants, vitamins E and C, and spontaneous superoxide generation, vitamin C and total antioxidant capacity were measured before and after treatment. RESULTS: The treatment of the patients with antioxidants resulted in a reduction in spontaneous superoxide generation (pre-treatment 8.41+/-0.7 nmol/10(6) cells; post-treatment 5.64+/-0.6 nmol/10(6) cells; P<0.05). There was no significant difference in the superoxide generation from normal controls who did not receive treatment, measured prior to commencement of the study and 10 days later (first reading 4.81+/-0.5 nmol/10(6) cells; second reading 5.32+/-0.4 nmol/10(6) cells; P>0.05). Total antioxidant capacity increased significantly following treatment with vitamins C and E (555.4+/-142 vs. 668.6+/-186 micromol/l trolox equivalent; P=0.01) as did vitamin C concentrations (56.5+/-27 vs. 137.7+/-64 micromol/l; P=0.002). CONCLUSIONS: In this preliminary study, the treatment of patients with antioxidants, vitamins E and C, reduced neutrophil generation of superoxide and suggests that antioxidants may have an important role as adjuvant therapy. The evidence presented should form the basis of a larger randomized placebo-controlled trial of vitamins E and C as adjuvant therapy in patients with ANCA-associated systemic vasculitis.

Adult↗
PubMed2002

[Fallopian tube torsion: five cases with no other element].

Isolated Fallopian tube torsion is extremely rare and diagnosis is difficult. Laparoscopy is necessary, but surgery is often performed too late to preserve the tube. Five cases of Fallopian tube torsion with no other element are presented. Diagnostic difficulties, causes, ultrasonographic findings and treatment are discussed. Early diagnosis and surgical intervention is mandatory when exceptional isolated Fallopian tube torsion is suspected particularly in a nulliparous young woman.

Abdominal Pain↗
PubMed2001

IgG from myeloperoxidase-antineutrophil cytoplasmic antibody-positive patients stimulates greater activation of primed neutrophils than IgG from proteinase 3-antineutrophil cytosplasmic antibody-positive patients.

OBJECTIVE: Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) have been reported to be pathologically and clinically different. The aim of this study was to assess whether these differences could be explained by differing abilities of proteinase 3-antineutrophil cytoplasmic antibody (PR3-ANCA)-positive IgG preparations or myeloperoxidase-ANCA (MPO-ANCA)-positive IgG preparations to activate neutrophils (polymorphonuclear cells [PMN]) in vitro. METHODS: Using Percoll density gradients, PMN were isolated (concentration 2 x 10(6)/ml) and primed with cytochalasin B (1 ng/ml) and tumor necrosis factor alpha (TNFalpha; 2 ng/ml). The PMN were activated with 200 microg/ml of normal IgG or ANCA. Activation was determined by 1) superoxide anion generation as determined by the superoxide dismutase-inhibitable reduction of ferricytochrome c, 2) monitoring fluxes in Ca2+ concentration using Fura 2-AM-loaded PMN, and 3) degranulation using an MPO assay. Surface expression of PR3 and MPO was determined by fluorescence-activated cell sorter analysis. ANCA isotypes were investigated by enzyme-linked immunosorbent assay. RESULTS: Activation of PMN by MPO-ANCA-positive IgG preparations compared with PR3-ANCA-positive IgG preparations resulted in greater generation of superoxide anions (MPO-ANCA-positive IgG preparations 9.13 +/- 0.39 nmoles [mean +/- SEM], PR3-ANCA-positive IgG preparations 6.32 +/- 0.35 nmoles; P < 0.001), Ca2+ fluxes (MPO-ANCA-positive IgG preparations 0.735 +/- 0.10, PR3-ANCA-positive IgG preparations 0.33 +/- 0.098; P < 0.01), and MPO degranulation (MPO-ANCA-positive IgG preparations 251.98 +/- 26.7 ng, PR3-ANCA-positive IgG preparations 145.19 +/- 19.4 ng; P < 0.001). The increased activation seen with MPO-ANCA-positive IgG preparations was not due to increased expression of MPO on the cell surface, because following TNFalpha priming PR3 was expressed on significantly more cells than was MPO (PR3 expression 54.2 +/- 5.18%, MPO 31.6 +/- 3.55%; P < 0.001). IgG1 and IgG4 were the predominant isotypes in both MPO-ANCA-positive IgG preparations and PR3-ANCA. MPO-ANCA contained significantly more IgG1 than did PR3-ANCA, and PR3-ANCA-positive IgG preparations contained significantly more IgG3. CONCLUSION: In vitro MPO-ANCA-positive IgG preparations are more activating than PR3-ANCA-positive IgG preparations. The increased activation cannot be explained by increased MPO expression on the cell surface or greater IgG3 present in MPO-ANCA-positive IgG preparations. Differences in activation of PMN by these antibodies may determine some differences between WG and MPA.

Adult↗
PubMed2001

Leukocyte-endothelial interactions in antineutrophil cytoplasmic antibody-associated systemic vasculitis.

The etiology of ANCA-associated vasculitis is unknown. Currently, it is believed that disease may be triggered by infection with the release of proinflammatory cytokines in genetically susceptible individuals. Priming of PMNs and endothelial cells by these cytokines allows ANCAs to activate PMNs, with damage localized to the endothelium, resulting in early lesions. Damage and activation of endothelial cells produces proinflammatory chemokines and cytokines with influxes of monocytes and T cells that intensify endothelial damage. In the kidney, these changes eventually lead to crescent formation. Antigen-specific memory T cells persist after disease remission with the potential of reactivation and disease relapse. Although our understanding of the pathophysiologic mechanisms of ANCA-associated vasculitis is far greater now than when ANCAs were first identified in 1982, more experimental work in combination with clinical observations is required to further elucidate these mechanisms.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2001

Neutrophil priming and apoptosis in anti-neutrophil cytoplasmic autoantibody-associated vasculitis.

BACKGROUND: Interactions between anti-neutrophil cytoplasmic autoantibody (ANCA) and primed neutrophils (PMNs) may be central to the pathogenesis of primary small vessel vasculitis. PMNs from patients are primed, expressing proteinase 3 (PR3) on the cell surface, which permits interaction with ANCA. In vitro ANCA activates primed PMN to degranulate and generate a respiratory burst. Resultant reactive oxygen species are important in triggering apoptosis, but the fate of PMN in ANCA-associated vasculitis is unknown. Failure to remove apoptotic PMN in a nonphlogistic manner may sustain the inflammatory response. METHODS: PMNs from patients or controls were isolated, and the basal production of superoxide was measured by the superoxide dismutase-inhibitable reduction of ferricytochrome C. ANCA antigen expression on apoptotic PMN was assessed at 0, 12, and 18 hours by flow cytometry using dual staining with FITC-conjugated annexin V and PE-conjugated anti-murine IgG against monoclonal ANCA. Apoptosis was also assessed by morphology. In further studies, apoptotic PMNs were opsonized with monoclonal anti-myeloperoxidase (MPO) or anti-proteinase-3 (PR3) or irrelevant isotype-matched IgG (N IgG) and phagocytosis by macrophages was measured using interaction assays. Cytokines interleukin-8 (IL-8) and interleukin-1 were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Proteinase-3 expression (active 63.04 +/- 5.6% of total number of cells, remission 51.47 +/- 7.9% of total number of cells, control 17.7 +/- 4.7% of total number of cells, P < 0.05) and basal superoxide production (active 6.9 +/- 0.8 nmol/L x 10(6) cells, remission 5.15 +/- 0.4 nmol/L/10(6) cells, control 3.63 +/- 0.3 nmol/L/10(6) cells, P < 0.001) were significantly greater with freshly isolated PMN from patients than controls. PR3 expression and superoxide generation were positively correlated. PMN from patients with active disease became apoptotic at a greater rate than those of controls (at 18 hours, patients 72.3 +/- 3.9% apoptosis, controls 53.2 +/- 2.7% apoptosis, P < 0.05). PR3 and MPO expression were significantly greater on PMN isolated from patients at 12 and 18 hours. Opsonization of apoptotic PMN with ANCA significantly enhanced recognition and phagocytosis by scavenger macrophages (anti-MPO 88.95 +/- 6.27, anti-PR3 93.98 +/- 4.90, N IgG 44.89 +/- 3.44, P < 0.01) with increased secretion of IL-1 (anti-PR3 34.73 +/- 6.8 pg/mL, anti-MPO 42.01 +/- 12.3 pg/mL, N IgG 8.04 +/- 6.3 pg/mL, P < 0.05) and IL-8 (anti-PR3 8.97 +/- 0.93 ng/mL, anti-MPO 8.45 +/- 1.46 ng/mL, N IgG 0.96 +/- 0.15 ng/mL, P < 0.01). CONCLUSION: In vivo circulating PMNs are primed as assessed by PR3 expression and basal superoxide production, thereby enhancing their inflammatory potential. These PMNs undergo apoptosis more readily, at which times they express PR3 and MPO on their surface. These antigens may then provide targets for ANCA. Opsonization of apoptotic PMN will enhance clearance by macrophages but will also trigger the release of pro-inflammatory cytokines that may contribute to chronic inflammation.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2001

Development and progression of malignancy in human colon tissues are correlated with expression of specific Ca(2+)-binding S100 proteins.

The expression levels of seven different S100 proteins (S100A1, S100A2, S100A3, S100A4, S100A5, S100A6, and S100B) were characterized by immunohistochemistry in the epithelial versus connective tissues of a series of 35 colon specimens, including 6 normal samples, 5 adenomas with low-grade dysplasia, 5 adenomas with high-grade dysplasia, and 19 cancers. The results showed that S100A2, S100A3, and S100B proteins could not (or only marginally) be detected in colon tissues. On the other hand, the expression of S100A6 increased in epithelial tissues directly proportional to the increase of malignancy. The percentage of epithelial (or connective tissue) cells expressing S100A4 significantly decreased as the malignancy grade increased. The expression level of S100A1 proteins was somewhat higher in the connective tissues of normal cases and adenomas with low-grade dysplasia than in adenomas with high-grade dysplasia and cancers. This pattern of expression was not observed in epithelial tissues. While the node-positive cancers did not express S100A1, about half of the node-negative specimens did. The expression levels of S100A5 were similar in different epithelial tissues. However, in the connective tissues the expression levels decreased inversely proportional to the increase in pathological grading of the specimens. Therefore, the present study implicates several S100 proteins as useful tools for histochemical typing of colon cancer malignancy development.

Adenoma↗
PubMed2000

Pathogenesis of ANCA-associated systemic vasculitis.

The aetiology of primary systemic vasculitides remains unknown. Recent advances have been made in the understanding of relevant mechanisms of inflammation, particularly the role of the endothelium and interactions with inflammatory mediators and immune effector cells. In Wegener's granulomatosis and microscopic polyangiitis the evidence suggests an autoimmune inflammatory process, characterized by an early lesion involving neutrophils and endothelial cells as both targets and active participants; priming of neutrophils and endothelial cells allows ANCA to activate neutrophils with damage localized to the endothelium. In the absence of immune complex deposition, the role of the ANCA is particularly intriguing. Endothelial cell damage and activation produces pro-inflammatory mediators with influx monocytes and T cells intensifying damage. Increased understanding of the pathogenesis of systemic vasculitis is likely to provide the basis for the use of more selective immunomodulatory therapies in the future.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2000

Antineutrophil cytoplasmic antibodies induce reactive oxygen-dependent dysregulation of primed neutrophil apoptosis and clearance by macrophages.

This study assessed whether anti-neutrophil cytoplasmic antibodies (ANCAs) interfere with the safe deletion of neutrophils by apoptosis and phagocytic clearance. Tumor necrosis factor (TNF)-primed neutrophils were incubated with normal IgG (N IgG) or ANCA IgG for up to 36 hours. Compared with N IgG, ANCAs accelerated constitutive apoptosis of TNF-alpha primed neutrophils, as assessed by morphology and confirmed by DNA laddering pattern on gel electrophoresis, and accelerated progression to secondary necrosis. The accelerated apoptosis induced by ANCA was dependent on reactive oxygen species generation, as primed neutrophils from patients with chronic granulomatous disease failed to show an effect of ANCAs on apoptosis. However, there was no change in the rate at which neutrophils exhibited annexin V binding, indicating that externalization of phosphatidylserine was not accelerated by ANCAs. Furthermore, when ANCA-treated primed neutrophils were interacted with human or murine peritoneal macrophages after 12 hours there was significantly less phagocytosis by human macrophages and no difference in phagocytosis by murine peritoneal-derived macrophages when compared with N IgG-treated controls. In conclusion, ANCAs accelerate apoptosis and secondary necrosis in TNF-primed neutrophils by a mechanism dependent on the generation of reactive oxygen species, with uncoupling of nuclear and surface membrane changes, resulting in a "reduced window of opportunity" for phagocytic recognition and engulfment before disintegration.

Animals↗
PubMed2000

Experience of corporate medical assistance clinics during the Centennial Olympic Games, Atlanta, 1996.

The health of travelers returning home from developing countries has received increased attention in recent years. Much of this attention has centered on immunizations, malaria chemoprophylaxis and treatment of traveler's diarrhea. In contrast, there are very few data on the health problems of international travelers to developed countries such as the United States. We studied the experience of two corporate medical assistance clinics established for both national and international travelers to Atlanta, Georgia during the Centennial Summer Olympic Games in 1996.

Adolescent↗
PubMed2000

Homocamptothecin, an E-ring-modified camptothecin, exerts more potent antiproliferative activity than other topoisomerase I inhibitors in human colon cancers obtained from surgery and maintained in vitro under histotypical culture conditions.

Topoisomerase I (Topo I) is overexpressed in cancer colon tissues compared with normal colon tissues. Several anti-Topo I inhibitors are already successfully used in the clinic. We illustrate here the antiproliferative activity of a new class of Topo I inhibitors, i.e., E-ring-modified camptothecins with enhanced lactone stability (L. Lesueur-Ginot et al., Cancer Res., 59: 2939-2943, 1999). Forty-three human colon cancers were obtained from surgical resection and maintained under organotypical culture conditions for 48 h. Cell proliferation was assessed in these ex vivo tumor tissue cultures by tritiated thymidine autoradiography. As a validation of the methodology, we first analyzed in our model the antiproliferative activity of two clinically active topoisomerase II (Topo II) inhibitors, Adriamycin and etoposide, which are not active for colon cancers; and three Topo I inhibitors, camptothecin (CPT) and two clinically active compounds (especially for colon cancers), i.e., topotecan and the active metabolite of irinothecan, SN-38. We then compared the antiproliferative activity of CPT, topotecan, and SN-38 against those of two investigational E-ring-modified camptothecins, i.e., BN80245 and BN80915. Three concentrations (1, 10, and 100 nM) were studied for each compound. The results indicate that the three Topo I inhibitors used as references, i.e., CPT, irinothecan, and SN-38, were much more active than the two Topo II inhibitors, i.e., Adriamycin and etoposide, with SN-38 being the most efficient. The two investigational compounds BN80245 and BN80915 exerted higher antiproliferative activity than the three anti-Topo I reference compounds, with the highest activity observed for BN80915.

Antineoplastic Agents↗
PubMed2000

The effect of the general practice registrar year on perceived skills in palliative care in the West Midlands.

OBJECTIVES: To ascertain the effect of 12 months spent as a GP registrar on perceived skills in palliative care. DESIGN: A previously validated questionnaire for use with medical undergraduates is modified and used to survey perceived skills in five aspects of providing palliative care in five different scenarios at two points during the 12-month period of general practice vocational training where no specific teaching intervention is conducted. SETTING: The West Midlands. PARTICIPANTS: 210 GP registrars. RESULTS: Perceived skill ratings were seen to significantly increase during the 12-month period, but anxiety in caring for the dying did not significantly decrease. Ratings of skills were lowest when caring for a child dying with leukaemia or a young adult dying with AIDS. In addition, other important variables which had a statistically significant influence were gender and age, but interestingly not the number of previous senior house officer (SHO) posts undertaken or whether the respondent had had formal teaching on the subject in the past. CONCLUSION: It might therefore be postulated that training as a GP registrar has an important impact on the development of perceived skills in palliative care.

Adult↗