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1.  Treatment of unresectable intrahepatic cholangiocarcinoma with yttrium-90 radioembolization: A systematic review and pooled analysis 
Radioembolization with yttrium-90 microspheres offers an alternative treatment option for patients with unresectable intrahepatic cholangiocarcinoma (ICC). However, the rarity and heterogeneity of ICC makes it difficult to draw firm conclusions about treatment efficacy. Therefore, the goal of the current study is to systematically review the existing literature surrounding treatment of unresectable ICCs with yttrium-90 microspheres and provide a comprehensive review of the current experience and clinical outcome of this treatment modality. We performed a comprehensive search of electronic databases for ICC treatment and identified 12 studies with relevant data regarding radioembolization therapy with yttrium-90 microspheres. Based on pooled analysis, the overall weighted median survival was 15.5 months. Tumour response based on radiological studies demonstrated a partial response in 28% and stable disease in 54% of patients at three months. Seven patients were able to be downstaged to surgical resection. The complication profile of radioembolization is similar to that of other intra-arterial treatment modalities. Overall survival of patients with ICC after treatment with yttrium-90 microspheres is higher than historical survival rates and shows similar survival to those patients treated with systemic chemotherapy and/or trans-arterial chemoembolization therapy. Therefore, the use of yttrium-90 microspheres should be considered in the list of available treatment options for ICC. However, future randomized trials comparing systemic chemotherapy, TACE and local radiation will be required to identify the optimal treatment modality for unresectable ICC.
PMCID: PMC4316196  PMID: 25449754
Cholangiocarcinoma; Radioembolization; Yttrium-90 microsphere
2.  The potential role of human endogenous retrovirus K10 in the pathogenesis of rheumatoid arthritis: a preliminary study 
Annals of the Rheumatic Diseases  2005;65(5):612-616.
To examine whether human endogenous retrovirus K10 is associated with autoimmune rheumatic disease.
A novel multiplex reverse transcription polymerase chain reaction (RT‐PCR) system was developed to investigate HERV‐K10 mRNA expression in patients with rheumatoid arthritis.
40 patients with rheumatoid arthritis, 17 with osteoarthritis, and 27 healthy individuals were recruited and total RNA was extracted from peripheral blood mononuclear cells (PBMCs) and analysed using multiplex RT‐PCR for the level of HERV‐K10 gag mRNA expression. Southern blot and DNA sequencing confirmed the authenticity of the PCR products.
Using the histidyl tRNA synthetase (HtRNAS) gene as a housekeeping gene in the optimised multiplex RT‐PCR, a significantly higher level of HERV‐K10 gag mRNA expression was found in rheumatoid arthritis than in osteoarthritis (p = 0.01) or in the healthy controls (p = 0.02).
There is enhanced mRNA expression of the HERV‐K10 gag region in rheumatoid arthritis compared with osteoarthritis or healthy controls. This could contribute to the pathogenesis of rheumatoid arthritis.
PMCID: PMC1798125  PMID: 16192292
human endogenous retroviruses; rheumatoid arthritis; peripheral blood mononuclear cells; histidyl tRNA synthetase
3.  Sensitivity of quantitative 1H magnetic resonance spectroscopy of the brain in detecting early neuronal damage in systemic lupus erythematosus 
Annals of the Rheumatic Diseases  2001;60(2):106-111.
OBJECTIVE—To quantify N-acetylaspartate (NAA), total creatines (tCr), total cholines (tCho), and myo-inositol (mI) levels in normal and abnormal appearing white matter of patients with neuropsychiatric systemic lupus erythematosus (NPSLE) in order to determine the specific changes in metabolite concentrations.
METHODS—Axial proton density and T2 weighted magnetic resonance images, and short echo time (TE 30 ms) 1H spectra were acquired with a GE SIGNA 1.5 T magnetic resonance system. Concentrations of NAA, tCr, tCho, and mI were determined, using brain tissue water as a reference, from nine patients (seven female, mean age 40.3 years, range 16-65) with NPSLE and eight healthy women (mean age 43 years, range 31-65).
RESULTS—A significant rise of tCho (12.4%, p<0.05) and mI (31.4%, p<0.005) and a significant reduction in NAA (−12%, p<0.05) was found in normal appearing white matter compared with controls. Analysis according to severity of the clinical NPSLE features (subgrouped as major or minor) showed that SLE major had reduced NAA compared with SLE minor (−18.4%, p<0.05) and controls (−20%, p<0.005). The SLE major group showed a significant rise of mI (32%, p<0.01) and the SLE minor group a significant increase in tCho (18.6%, p<0.05) compared with controls. Longitudinal analysis of brain metabolites in normal appearing white matter showed consistent abnormalities in NAA, tCho, and mI in a patient with stable clinical features and a constant rise of tCho, but transient rise of mI was seen during a flare of disease in another patient.
CONCLUSION—Quantitative 1H magnetic resonance spectroscopy (MRS) suggests a particular course of neurometabolite changes that precedes irreversible reductions in NAA and permanent neuronal loss. Initially, in patients with SLE minor, there is a significant rise in tCho and a trend (reversible) for mI also to be raised. In patients with SLE major the NAA is significantly and permanently reduced and mI is significantly raised, whereas the tCho levels are near normal. Further investigations are needed to determine how specific MRS is as a clinical marker for brain disturbance in SLE.

PMCID: PMC1753471  PMID: 11156541
5.  Increased IgA rheumatoid factor and VH1 associated cross reactive idiotype expression in patients with Lyme arthritis and neuroborreliosis 
Annals of the Rheumatic Diseases  1999;58(12):757-761.
OBJECTIVE—To investigate whether autoreactive mechanisms occur in Lyme disease (LD) by determining IgA, IgG and IgM rheumatoid factor (RF) concentrations and RF associated cross reactive idiotype (CRI) expression in the serum of LD patients, with comparison to patients with rheumatoid arthritis (RA).
METHODS—The RF isotype profiles were determined in 59 patients with LD; erythema migrans (EM) (n=19), neuroborreliosis (NB) (n=20) and Lyme arthritis (LA) (n=20). Mouse monoclonal antibodies (mAbs) G6 and G8 (VH1 gene associated), D12 (VH3 gene associated) and C7 (VκIII gene associated) were then used to determine the RF associated CRI expression on IgM antibodies in 16 of these LD patients (eight seropositive for RF); (EM (n=3), NB (n=6), LA (n=7)).
RESULTS—Seven (18%) patients with either NB or LA had increased concentrations of IgA RF compared with none with EM. Significant differences in the number of patients with raised concentrations of IgG RF or IgM RF were not found between the LD patient groups. Five (3NB, 1LA and 1 EM) (31%) and three (2NB and 1LA) (19%) of LD patients had raised concentrations of the CRIs recognised by mAbs G6 and G8, respectively. These CRIs were detected in LD sera both with and without raised concentrations of RF and were not demonstrated on anti-Borrelia burgdorferi antibodies using ELISA. No LD sera tested had raised concentrations of the determinants recognised by mAbs C7 or D12.
CONCLUSION—Significantly raised concentrations of IgA RF and increased use of VH1 germline gene associated CRIs are found on IgM antibodies in the serum of LD patients. These data indicate the recruitment of autoreactive B lymphocytes in some patients with the later stages of LD.

PMCID: PMC1752811  PMID: 10577962
7.  Rheumatoid factors: where are we now? 
Annals of the Rheumatic Diseases  1997;56(5):285-286.
PMCID: PMC1752383  PMID: 9175927
8.  Use of complementary therapies by patients attending musculoskeletal clinics. 
Patients with musculoskeletal disorders commonly seek treatment outside orthodox medicine (complementary therapy). In patients attending hospital clinics we investigated the prevalence of such behaviour and the reasons for it. Patients attending rheumatology and orthopaedic clinics who agreed to participate were interviewed on the same day by means of a structured questionnaire in three sections: the first section about demographic characteristics; the second about the nature and duration of the complaint, the length of any treatment and whether the patient was satisfied with conventional treatment; and the third about the use of complementary medicine, the types of therapy that had been considered and the reasoning behind these decisions. The data were examined by univariate and bivariate analysis as well as logistic regression multivariate analysis. 166 patients were interviewed (99% response rate) and the predominant diagnosis was rheumatoid arthritis (22.3%). 109 patients (63%) were satisfied with conventional medical treatment; 63 (38%) had considered the use of complementary therapies, and 47 (28%) had tried such a therapy. 26 of the 47 who had used complementary therapy said they had gained some benefit. Acupuncture, homoeopathy, osteopathy and herbal medicine were the most popular types of treatment to be considered. Patients of female gender (P = 0.009) and patients who had expressed dissatisfaction with current therapies (P = 0.01) were most likely to have considered complementary medicine. These results indicate substantial use of complementary therapy in patients attending musculoskeletal disease clinics. The reasons for dissatisfaction with orthodox treatment deserve further investigation, as does the effectiveness of complementary treatments, which must be demonstrated before they are integrated with orthodox medical practice.
PMCID: PMC1297030  PMID: 10319029
9.  Is walking to the North Pole good for you? 
Annals of the Rheumatic Diseases  1994;53(10):703-704.
PMCID: PMC1005443  PMID: 7979589
10.  Lyme arthritis. 
Annals of the Rheumatic Diseases  1994;53(9):553-556.
PMCID: PMC1005402  PMID: 7979590
11.  Fever of unknown origin in childhood: difficulties in diagnosis. 
Annals of the Rheumatic Diseases  1994;53(7):429-433.
We have described a child with systemic onset juvenile chronic arthritis who presented initially with fever of unknown origin. Treatment of a presumed infection led to a severe allergic response with Stevens-Johnson syndrome, renal failure and DIC. This reaction obscured the features of the underlying disease and delayed the diagnosis.
PMCID: PMC1005364  PMID: 7944613
13.  Expression of public idiotypes in patients with Lyme arthritis. 
Annals of the Rheumatic Diseases  1993;52(3):199-205.
OBJECTIVE: Joints are often affected in Lyme disease and in some instances this may be due to immune autoreactivity. To characterise further the immune response in this disease investigations were carried out to determine the expression of three public idiotypes on serum immunoglobulins in patients with Lyme disease during the development of varying degrees of arthritis. METHODS: The expression of idiotypes (Ids) 16/6, BEG2, and PR4, first identified on monoclonal antibodies to DNA, was determined by an enzyme linked immunosorbent assay (ELISA) in serial blood samples from 12 patients with Lyme disease over a mean period of six years during the development of a variety of arthritic symptoms, and in serum samples from healthy control subjects and control subjects with systemic lupus erythematosus. RESULTS: Expression of serum IgM or IgG public Ids 16/6 and BEG2 was significantly increased in patients with Lyme disease. IgA Id 16/6 expression, in contrast, was significantly increased only during episodes of arthritis and was also related to its severity. IgM and IgG Id 16/6 expression was related to their respective total immunoglobulin concentration and, in the case of IgM, to the level of IgM antibodies to Borrelia burgdorferi, whereas similar findings were not apparent with IgA antibodies. This may indicate that the IgA response is related to the pathogenesis of arthritis, especially as total IgA and IgA Id 16/6 levels were found to increase over the duration of disease. Sequential analysis of antibodies also showed restriction in the expression of Id 16/6 as it was never found on all immunoglobulin isotypes at the same time, and Id PR4 was never expressed. Ids 16/6 and BEG2 expression, however, may be associated as seven patients expressed these idiotypes simultaneously. CONCLUSIONS: These data indicate the use of public idiotypes in the immune response against B burgdorferi, which may be restricted in terms of idiotype class and isotype expression, and a possible association between IgA antibodies bearing Id 16/6 with arthritis.
PMCID: PMC1005017  PMID: 8484672
14.  No evidence to implicate Borrelia burgdorferi in the pathogenesis of dilated cardiomyopathy in the United Kingdom. 
British Heart Journal  1994;71(5):459-461.
OBJECTIVE--To determine whether Borrelia burgdorferi is implicated in the pathogenesis of dilated cardiomyopathy in the United Kingdom. DESIGN--A controlled prospective study. Patients' notes were reviewed for evidence of Lyme disease and serum samples were tested by enzyme linked immunoadsorbent assay (ELISA) for antibodies to B burgdorferi. Samples with raised antibody concentrations were subsequently analysed by immunoblotting to determine their antibody binding specificity. SETTING--Tertiary referral centre. PATIENTS--97 consecutive patients with dilated cardiomyopathy diagnosed according to World Health Organisation criteria were studied. Serum samples were taken from two matched control groups. The first group (n = 38) was age, sex, and geographically matched. The second control group (n = 39) was environmentally matched and consisted of members of the patients' own households. MAIN OUTCOME MEASURES--Clinical evidence of Lyme disease. Presence of raised antibody concentrations to B burgdorferi. RESULTS--No patients had a previous illness compatible with Lyme disease. Analysis of the ELISA data showed eight of 97 patients with dilated cardiomyopathy (8.2%) and two of 77 controls (3.9%) had raised antibody concentrations. Immunoblot analysis, however, did not show binding patterns consistent with the presence of IgG specific for B burgdorferi in any of these samples. CONCLUSIONS--There was no clinical or serological evidence to implicate B burgdorferi in the pathogenesis of idiopathic dilated cardiomyopathy in the United Kingdom. In the absence of specific symptoms or likely exposure to B burgdorferi routine serological testing for Lyme disease in this group of patients is not recommended. Furthermore, raised antibodies to B burgdorferi are not diagnostic of active infection and ELISA results should be interpreted with caution unless specific B burgdorferi antibody bands have been found by immunoblot analysis.
PMCID: PMC483724  PMID: 8011411
15.  Changes in normal glycosylation mechanisms in autoimmune rheumatic disease. 
Journal of Clinical Investigation  1992;89(3):1021-1031.
To investigate potential mechanisms controlling protein glycosylation we have studied the interrelationship between lymphocytic galactosyltransferase (GTase) activity and serum agalactosylated immunoglobulin G levels (G(0)) in healthy individuals and patients with rheumatoid arthritis and non-autoimmune arthritis. In RA there was reduced GTase activity and increased G(0). A positive linear correlation between B and T cell GTase was found in all individuals. The relationship between GTase and G(0) was found to be positive and linear in the control population and negative and linear in the RA population. Sulphasalazine therapy maintained normal levels of GTase and caused a reduction in G(0) in the RA population. IgG anti-GTase antibodies (abs) were significantly increased in the RA population, whereas IgM anti-GTase abs were significantly decreased in both the RA and the non-autoimmune arthritis groups. These data describe a defect in RA lymphocytic GTase, with associated abnormal G(0) changes, which is corrected by sulphasalazine. A possible regulatory mechanism controlling galactosylation in normal cells is suggested, in which there is parallel control of B and T cell GTase. IgM anti-GTase abs may be integrated into this normal regulatory process. This is disrupted in RA, where the positive feedback between GTase and G(0) is lost and there is an associated increase in IgG anti-GTase abs, which may result from isotype switching as IgM anti-GTase abs are reduced. We suggest that these mechanisms are of relevance to the pathogenesis of RA, and that their manipulation may form part of a novel therapeutic approach.
PMCID: PMC442952  PMID: 1347295
17.  Pseudohyperkalaemia 
PMCID: PMC1417886  PMID: 3931852
18.  Inhibition of lymphocyte capping and transformation by propranolol and related compounds. 
1 The effects of propranolol on phytohaemagglutinin (PHA)-induced transformation of murine T lymphocytes and capping of anti-IgG on the surface of murine B lymphocytes have been examined. 2 A 50% inhibition of transformation was observed with 10(-5) M propranolol, whereas a higher concentration, of the order of 10(-3) M propranolol was required to inhibit capping by 50%. The (+)-and (-)-isomers of propranolol proved equipotent in these respects, and the relative potencies of selected analogues of propranolol (alprenolol, oxprenolol, metoprolol, practolol, and sotalol) coincided with their potencies as membrane stabilizers; however, lymphocyte transformation was consistently more sensitive than capping. 3 Similar effects were also seen with quinidine, chlorpromazine and lignocaine, and it was concluded that the inhibition of both lymphocyte functions was due to the membrane stabilizing actions of propranolol.
PMCID: PMC2071544  PMID: 6112036
19.  Tanapox. A serological survey of the lower Tana River Valley. 
The Journal of Hygiene  1979;83(2):273-276.
Sera collected from the indigenous population of the Tana River valley during the Tana River Expedition in 1976 were examined for neutralizing antibody to Tanapox virus. Antibody was found in 9.2% of the population in infected areas. This result and the presence of antibody in four children indicated that infection had continued to occur in the area since the 1962 outbreak.
PMCID: PMC2129896  PMID: 226625
20.  An open-label dosing study to evaluate the safety and effects of a dietary plant-derived polysaccharide supplement on the N-glycosylation status of serum glycoproteins in healthy subjects 
The functional role of dietary carbohydrates in nutrition is one of the most complex and at times controversial areas in nutritional science. In-vitro and in-vivo studies suggest that certain dietary saccharide biopolymers can have bifidogenic and or immunomodulatory effects, and that some could represent preferential substrates or precursors that can impact cellular glycosylation.
Examine the impact of oral ingestion of a standardized dietary plant-derived polydisperse polysaccharide supplement (Advanced Ambrotose powder (AA)) on the N-glycosylation status of serum glycoproteins in a cohort of healthy individuals.
An open-label study was carried out. This study was in two phases: pilot study (n=6 individuals) to assess safety and dose, and a larger study (n=12) to evaluate specific glycosylation changes. Serum N-glycosylation profiles, using mass spectrometry, were monitored at weekly intervals, for 7 weeks, to evaluate baseline levels and normal fluctuations. The individuals were then monitored for a further 7 weeks, during which time increasing doses of AA were ingested (1.3–5.2 g/day).
No adverse events were encountered. AA supplementation resulted in distinct changes in the relative intensities of seven biantennary N-glycans (P<0.001), and a significant overall shift towards increased sialylation. Regression analysis revealed a dose-dependent decrease in mono- and di-galactosylated structures (coefficient −0.130 decrease/week: P=0.02 and −0.690: P=0.005), and a concomitant increase in disialylated glycans ( × 1.083: P<0.05).
Supplementation with the dietary plant-derived polysaccharides in AA resulted in significant changes in serum protein N-glycosylation in healthy individuals. How this occurs and whether it has biological significance remains to be evaluated.
PMCID: PMC3087895  PMID: 21224866
dietary plant polysaccharides; Serum glycosylation; N-glycans; dietary fiber; glycomodifications; sialylation

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