Dose-Response Relationship in Differentiated Thyroid Cancer Patients Undergoing Radioiodine Treatment Assessed by Means of 124I PET/CT.

UNLABELLED: The dose-response relationship in a fixed-activity approach generally applied in the treatment of differentiated thyroid cancer was assessed using (124)I PET/CT. METHODS: Pretherapeutic (124)I PET/CT images of 47 patients scheduled for radioiodine therapy were retrospectively analyzed. (124)I PET/CT images were acquired 24 and 96 h after oral administration of approximately 28 MBq of (124)I-sodium iodide. Lesions were identified as thyroid remnants or metastases (lymph node, lung, bone). After a neoteric segmentation technique allowing accurate volume estimation down to the (124)I PET spatial resolution of 0.15 mL was applied, lesions were divided into a known-volume group and a small-volume group. For the known-volume group, average lesion-absorbed dose (AD) values were calculated, whereas for the small-volume group a minimum lesion AD was estimated. Lesion response was determined on the basis of (124)I PET/CT and (131)I SPECT/CT follow-up images. A lesion not detectable on any of the follow-up images was considered a completely responding lesion. Differences in lesion AD estimations between completely and incompletely responding lesions were evaluated by Mann-Whitney U test. Moreover, receiver-operating-characteristic curves were used to test the performance of pretherapeutic (124)I PET/CT lesion AD for prediction of complete lesion response. RESULTS: In the approach of fixed radioiodine activity (3.0 ± 1.0 GBq), 89% of thyroid remnants and 69% of metastases responded completely. Except for the small-volume groups, the lesion AD of completely responding lesions was significantly higher than that of incompletely responding lesions. Using receiver-operating-characteristic curve analysis, it was shown that for the known-volume group, pretherapeutic (124)I PET/CT lesion dosimetry can be used as a prognostic tool to predict lesion-based (131)I therapy response with an area under the curve of 0.76 for remnants and 0.97 for metastases. The corresponding lesion AD threshold value maximizing correct complete response prediction was 90 Gy for remnants and 40 Gy for metastases. CONCLUSION: In a fixed-activity approach, a statistically significant dose-response relationship for both thyroid remnants and metastases using pretherapeutic (124)I PET/CT lesion dosimetry was found. The findings may be useful in patient management.

Belgian recommendations on ANA, anti-dsDNA and anti-ENA antibody testing.

Autoantibodies to nuclear antigens, i.e. antinuclear antibodies (ANA), antibodies to double-stranded DNA (dsDNA) and extractable nuclear antigens (ENA), are useful as diagnostic markers for a variety of autoimmune diseases. In March 2010, the Belgian national External Quality Assessment Scheme sent a questionnaire on ANA, anti-dsDNA and anti-ENA antibody testing designed by the Dutch EASI (European Autoimmunity Standardization Initiative) team, to all clinical laboratories performing ANA testing. Virtually all laboratories completed the questionnaire (97·7%, 127/130). This paper discusses the results of this questionnaire and provides valuable information on the state-of-the-art of ANA, anti-dsDNA and anti-ENA antibody testing as practiced in the Belgian laboratories. In addition, this work presents practical recommendations developed by the members of the advisory board of the scheme as a result of the outcome of this study.

Anti-cyclic citrullinated peptide antibodies: a comparison of different assays for the diagnosis of rheumatoid arthritis.

OBJECTIVES: Anti-cyclic citrullinated peptide (anti-CCP) antibodies are highly specific markers of rheumatoid arthritis (RA). Considering the heterogeneity of the target antigens involved, and the test platforms and conjugates proposed in commercial anti-CCP assays, we assessed the diagnostic performances of four fully automated anti-CCP assays in a cohort of patients with RA compared to patients with other autoimmune and inflammatory disorders. We also evaluated the agreement between the qualitative results of these immunoassays. METHOD: We evaluated three anti-CCP2 assays [Eurodiagnostica enzyme-linked immunosorbent assay (ELISA), Elecsys electrochemiluminescence immunoassay (ECLIA) on the Modular E170 Analyzer, and Zenit chemiluminescence immunoassay (CLIA) on the Zenit RA Analyzer] and one anti-CCP3 assay (Inova ELISA). ELISAs were performed on an automated workstation. Samples from 112 patients with RA and a disease control group of 136 patients (53 with autoimmune diseases, 65 non-autoimmune disorders, and 18 infectious diseases) were studied (included 161 samples submitted consecutively to the laboratory). RESULTS: At a fixed specificity of 92%, the anti-CCP3 assay presented the highest sensitivity (75%) compared to the anti-CCP2 assays evaluated (63-72%). The Zenit anti-CCP2 assay gave the most false-positive results (especially in patients with viral infections and connective tissue diseases). The agreement between assays ranged from 86.3% to 95.2% and Kappa coefficients ranged from 0.724 to 0.899. CONCLUSIONS: Recently released automated workstations provide a valuable alternative to ELISA to diagnose RA. However, differences in diagnostic performances are highlighted in our experience, especially for the Zenit assay. In our cohort, the anti-CCP3 assay gave slightly better performances than the anti-CCP2 assays (with the exception of the Zenit assay).

Diagnostic specificities and sensitivities of anti dsDNA, anti membrane DNA and anti nucleosomes autoantibodies.

The aim of this study is to evaluate, from 369 routine sera of SLE and control patients, the worth of anti double stranded nuclear DNA, anti nucleosomes autoantibodies and anti membrane DNA for the diagnosis of SLE. Cell membrane associated DNA (mDNA) has been described on B lymphocytes and monocytes, but not on T cells. Antibodies to mDNA were identified by an indirect immunofluorescence assay using a B cell line fixed but not permeabilised. At a 1:40 serum dilution, anti mDNA is almost associated with the diagnosis of systemic lupus erythematosus (SLE). Anti mDNA were shown to be different in specificity as compared with anti double stranded nuclear DNA. We compare its characteristics as diagnostic procedure to the conventional anti dsDNA antibody detection and to the recently introduced anti nucleosome antibody test documented as associated with SLE. It appears that the best sensitivity (0.65) and specificity (0.98) is given by the anti mDNA test.

The influence of health sector reform and external assistance in Burkina Faso.

Despite health reform and increasing public investment in the health sector, utilization of curative health services, immunization coverage and patient satisfaction with the public health care system are steadily decreasing in Burkina Faso. It seems that the health care system itself is "ill". This paper examines the major symptoms associated with this illness. The central thesis suggests that any further improvement of health care performance in Burkina Faso will be subject to profound central reform in the area of human resources and financial management of the sector. Such a broad reform package cannot be achieved through the current project approach, but a sector-wide approach (SWAp) does not seem to be realistic at the present time. Policy discussions at a level higher than the Ministry of Health could be beneficial for achieving better donor coordination and increasing the commitment of the Ministry of Health to a sector-wide approach. Health sector reform issues and priorities and the role of international cooperation are reviewed and discussed.

Evidence of autoantibodies to cell membrane associated DNA (cultured lymphocytes): a new specific marker for rapid identification of systemic lupus erythematosus.

OBJECTIVE: Autoantibodies to cell membrane associated DNA are described in systemic lupus erythematosus (SLE). The specificity of these antibodies differ from antibodies to nuclear DNA. METHODS: Using indirect immunofluorescence, a specific IgG was detected giving a characteristic pattern of continuous peripheral membrane fluorescence on cultured B-lymphocytes. RESULTS: This pattern was observed in 53 of 80 serum samples of SLE patients but absent in the serum samples of the control populations: 15 rheumatoid arthritis, 38 ankylosing spondylarthritis, 17 non-inflammatory osteopenic patients, and 224 blood donors. In 34 Sjögren syndrome's patients one only showed a positive test. The cmDNA specificity of these antibodies was confirmed by pattern extinction with DNAse but not RNase or protease pre-treatment of the cells. IgG to cmDNA, separated by absorption/elution from purified cmDNA immobilised on DEAE-nitrocellulose reproduced the immunofluorescence pattern pictures. Extensive serum depletion of anti-double strand or single strand DNA antibodies by absorption to cellulose bound ds- or ss-DNA affected marginally the pericellular fluorescence revealing some minor cross reactivity with nuclear DNA. Moreover, in SLE patients without detectable antibody to ds-DNA, pericellular fluorescence could be visible. CONCLUSION: This novel rapid immunofluorescence method may serve as an identification test of SLE patients. Given its positive (97.1%) and negative (92.9%) predictive value, sensitivity (66%) and specificity (99.5%), it improves on other diagnostic tests such as the detection of antibodies to Sm.

Antithyroid antibodies underlying thyroid abnormalities and miscarriage or pregnancy induced hypertension.

OBJECTIVE: To assess whether asymptomatic abnormalities, including thyroid auto-antibodies, were associated with an abnormal miscarriage rate or a poor obstetric outcome. DESIGN: Prospective study of thyroid auto-antibodies and thyroid function in an unselected obstetric population. SETTING: Saint-Pierrie Hospital, Brussels, Belgium. SUBJECTS: Seven hundred and thirty consecutive pregnant women attending the antenatal clinic. MAIN OUTCOME MEASURES: Miscarriage and pregnancy induced hypertension. RESULTS: Elevated antithyroperoxidase (TPO-Ab) and antithyroglobulin (TG-Ab) antibody titres are associated with an increased miscarriage rate. Also, asymptomatic thyroid abnormalities, mainly abnormal echo-structure but not antithyroid antibodies, are associated with pregnancy induced hypertension. CONCLUSION: The presence of thyroid auto-antibodies during pregnancy constitutes a marker of increased risk of miscarriage and poor obstetric prognosis.

Antibody affinity disturbance in the immunoglobulin immune response to mucosal antigenic stimulation in lung cancer. The Betalactoglobulin Model.

BACKGROUND: This study is a continuation of a recent study, in which a defect in the immunoglobulin G (IgG) response to some natural antigens (bovine betalactoglobulin [BLG] from cow's milk and antigen p1 from the house dust mite Dermatophagoïdes pteronyssinus), usually presented at the mucosal level, was documented in lung cancer patients. The present study further characterizes this difference in terms of antibody relative functional affinity in the BLG model. METHODS: Relative functional affinity was evaluated by solid-phase enzyme-linked immunosorbent assay in terms of the relationship between specific IgG retention, assessed with peroxidase-labeled protein A, and serial dilutions of IgG fractions isolated from 24 sera from lung cancer patients and 24 sera from healthy control subjects matched for their anti-BLG IgG antibody titers. The procedure was performed in the presence and absence of low concentrations of diethylamine, which was expected to prevent low-affinity antigen-antibody binding without affecting the binding of high-affinity antibodies. Anti-BLG IgG antibody affinity also was evaluated in 25 patients with early-stage lung cancer, before and after (5 +/- 1 week) complete surgical excision of the tumor. RESULTS: Results, expressed as the slope of the binding curves and their leftward shift induced by diethylamine, showed different antibody populations between the two groups. Control sera showed a heterogeneous population of anti-BLG IgG antibodies, including antibodies of higher (steeper slope) and lower (more gradual slope) functional affinity. Cancer sera exhibited a less heterogeneous population of anti-BLG IgG antibodies, mostly with lower functional affinity. No change was observed in anti-BLG IgG antibody affinity in the 25 lung cancer patients tested 5 +/- 1 week after complete surgical excision of the tumor. CONCLUSIONS: These results document a persistent qualitative immunologic disturbance in patients with lung cancer, regardless of the type and extent of tumor. The potential relationship between this observation and the development of lung cancer, however, is presently unknown.

Abnormal humoral immune response to mucosal antigenic stimulation in patients with lung cancer.

Previous studies have suggested an inverse relationship between atopy and cancer of mucosal surfaces. Atopy is classically assessed by detecting specific immunoglobulin E (IgE) antibodies against inhalant allergens. However, Platts-Mills recently proposed that atopy is the ability of an organism to recognize and to respond to limited doses of allergens presented at the mucosal level by producing not only IgE, but also immunoglobulin A and immunoglobulin G (IgG) antibodies. The authors compared the prevalence of atopy in 103 patients with lung cancer (a model of mucosal cancer), 51 patients with chronic obstructive pulmonary disease matched for age, sex, and smoking habits with patients with lung cancer, and 102 healthy control subjects. The authors investigated whether the IgG response to antigens presented at the mucosal level, exacerbated in atopic subjects, might inversely be decreased in patients with lung cancer. Serum IgE antibodies against five common inhalant allergens (Dermatophagoides pteronyssinus [Der p1], Aspergillus fumigatus, grass pollen, and cat and dog danders) were detected through a radioallergosorbent test assay. Serum IgG antibodies against allergens naturally presented at the mucosal level (respiratory mucosa with Der p1 and digestive mucosa with betalactoglobulin [BLG] and soya proteins [SP]) were measured through a solid phase enzyme-linked immunosorbent assay test. Atopic status was assessed in 19 patients (18.4%) with lung cancer, 9 patients (17.6%) with chronic obstructive pulmonary disease (COPD), and 18 healthy control subjects (17.6%). Distributions of specific IgG levels were represented on frequency histograms after natural logarithmic transformation and showed reduced levels of anti-Der p1 and anti-BLG IgG in the cancer population compared with the control populations but similar levels of anti-SP IgG. Influence of sex, age, smoking habits, histologic type of cancer, and its extent could be excluded. The authors' results show no difference in the prevalence of atopy between the three groups. They document a selective, rather than general, defect in the immune response initiated at the mucosal level in patients with lung cancer, the most frequent mucosal cancer in man.

Occupational asthma to spores of Pleurotus cornucopiae.

We report the case of a young man who developed severe asthma a few months after starting work in a factory producing a single type of mushroom: Pleurotus cornucopiae (a basidiomycete). Immunological investigations, performed with material recovered from the filtering devices of the mushroom's bed, led to demonstration of specific IgE and IgG against spore extracts and to isolation of one discriminant antigen (molecular weight: 10.5 kd). Current data concerning the underestimated role of the basidiomycetes in allergic asthma are reviewed.

Simple quantitative haemolytic microassay for determination of complement alternative pathway activation (AP50).

We describe here a simple, reliable and quantitative method to measure the alternative pathway (AP) dependent mode of complement activation for the lysis of rabbit erythrocytes. In the test the reciprocal of the plasma volume needed to destroy 50% of available rabbit erythrocytes is defined as the functional measure of this activity (AP50). The test was found to be highly reproducible both within and between assays with a coefficient of variation which was less than 5%. Sensitivity was also shown to be satisfactory and all of the plasma samples from the healthy blood donors which were tested could be assayed with precision. The specificity of the AP50 assay for AP complement activation was verified by the fact that a C4 affinity-depleted plasma gave an AP50 value within the normal range (52.8 U/ml) while a similar aliquot of the same plasma, affinity-depleted of factor B, gave an undetectable AP50 value (less than 10 U/ml). Furthermore, a sample was unable to lyse the target cells when heated to 50 degrees C or 56 degrees C, treatments which are known to destroy factor B and total haemolytic complement, respectively. To ensure inhibition of the classical pathway of activation. EGTA and MgCl2 were added during the assay. An advantage of this assay is that it is possible, using microplates, multipipettes and a spectrophotometer coupled to a computer, to semi-automate the procedure.

Biochemical thyroid profile in patients infected with the human immunodeficiency virus.

Over a 2-year period, thyroid function was studied in 102 patients infected with the human immunodeficiency virus (HIV) and in 102 age- and sex-matched controls with various infectious diseases. Biochemical abnormalities were observed in 1-20% of the patients, depending on thyroid indices, but thyroid disease (hypothyroidism) was diagnosed in only 1. Compared to controls, patients, especially those with the acquired immunodeficiency syndrome (AIDS), had a significant increase in serum thyroxine-binding globulin, a lower T3 and free thyroxine index, and a higher frequency of thyroglobulin antibodies.

Argon laser panretinal photocoagulation in ischemic central retinal vein occlusion. A 10-year prospective study.

We conducted a prospective, planned study of argon laser panretinal photocoagulation (PRP) in ischemic central retinal vein occlusion (CRVO) over a 10-year period in 123 eyes. On comparing the lasered eyes versus the nonlasered eyes, there was no statistically significant difference between the two groups in the incidence of development of angle neovascularization (NV), neovascular glaucoma (NVG), retinal and/or optic disc NV, or vitreous hemorrhage, or in visual acuity. Our study, however, did show a statistically significant (P = 0.04) difference in the incidence of iris NV between the two groups, with iris NV less prevalent in the laser group than in the nonlaser group, but only when the PRP was performed within 90 days after the onset of CRVO. The other parameter which showed a statistically significant difference between the two groups was the peripheral visual fields-the laser group suffered a significantly (P less than or equal to 0.03) greater loss than the non-laser group. We discuss the implications of these findings in light of the natural history of ischemic CRVO and of ocular NV. Since the original rationale for advocating PRP in ischemic CRVO was the proven beneficial effect of PRP on ocular NV in proliferative diabetic retinopathy, we also discuss the disparities in the disease process between ischemic CRVO and proliferative diabetic retinopathy and in their responses to PRP.

Retinal arteriolar changes in malignant arterial hypertension.

Experimental renovascular malignant arterial hypertension was produced by modified Goldblatt's procedures, in 60 rhesus monkeys, and various retinal arteriolar changes in hypertensive retinopathy were studied in detail (by serial ophthalmoscopy, and stereoscopic color fundus photography and fluorescein fundus angiography on long-term follow-up). The retinal arteriolar changes, in ophthalmoscopically visible arterioles, consisted of arteriolar sclerosis and associated changes, e.g., increased arteriolar tortuosity, arteriolar narrowing and in some animals occlusion and sheathing of the fine arterioles; we could find no evidence of localized or generalized 'spasm' in these retinal arterioles. Eyes in animals with accelerated arterial hypertension revealed focal dilatation and leakage of the retinal precapillary terminal arterioles (resulting in development of focal intraretinal periarteriolar transudates), and also occlusion of the terminal retinal arterioles (producing cotton-wool spots and associated intraretinal microvascular abnormalities). We discuss the controversial subjects of narrowing (particularly 'spasm') of ophthalmoscopically visible retinal arterioles and of fibrinoid necrosis in malignant hypertension.

Cotton-wool spots (inner retinal ischemic spots) in malignant arterial hypertension.

We produced experimental renovascular malignant arterial hypertension by modified Goldblatt's procedures, in 60 rhesus monkeys. Hypertensive retinopathy was studied in detail (by ophthalmoscopy, and stereoscopic color fundus photography and fluorescein fundus angiography on long-term follow-up). Cotton-wool spots (CWSs) were found to be an important, early retinal lesion. On ophthalmoscopy, they had a characteristic appearance. Fluorescein fundus angiography of these lesions revealed focal retinal capillary nonperfusion. The CWSs usually lasted for over 3 weeks and resolved within 6 weeks, leaving permanent obliteration of the retinal capillaries in their distribution, secondary intraretinal microvascular abnormalities, and retinal nerve fiber loss. We discuss pathogenesis and other features of CWSs. There is overwhelming evidence that CWSs are due to occlusion of the terminal retinal arterioles, resulting in acute focal inner retinal ischemia; hence the scientifically valid term for them would be 'inner retinal ischemic spots'.

Retinal lipid deposits in malignant arterial hypertension.

In 60 rhesus monkeys with experimental renovascular malignant arterial hypertension (25 one-kidney and 35 two-kidney model animals), we studied the so-called 'hard exudates' or white retinal deposits in detail (by ophthalmoscopy, and stereoscopic color fundus photography and fluorescein fundus angiography, on long-term follow-up). Some manifestation of hypertensive retinopathy developed in 19 one-kidney and 19 two-kidney animals, and white deposits formed in 14 and 5 monkeys, respectively. The onset of white deposits showed no correlation to severity of arterial hypertension or of retinopathy. All eyes with white deposits had antecedent macular or retinal edema. The deposits were everchanging, taking months or even more than a year to resolve. Our study suggests that in hypertensive retinopathy the white retinal deposits are most probably the result of exudative and/or neural degenerative processes. All the available pieces of evidence indicate that it is more appropriate to call the white deposits 'lipid deposits' than 'hard exudates'.

Macular lesions in malignant arterial hypertension.

We produced experimental renovascular malignant arterial hypertension by a modified Goldblatt's procedure in 60 rhesus monkeys (25 one-kidney model and 35 two-kidney model), and studied various macular lesions by detailed serial ophthalmoscopy, and stereoscopic color fundus photography and fluorescein fundus angiography on a long-term follow-up. The various lesions which developed in the macular region included retinal edema, cystic retinal changes, serous retinal detachment, retinal pigment epithelial changes (initially acute focal and later degenerative lesions), and lipid deposits. In addition to these, the usual retinal lesions associated with hypertensive retinopathy, e.g., focal intraretinal periarteriolar transudates, cotton-wool spots and retinal hemorrhages, were also frequently seen in the macular retina. Findings on the various lesions are described in detail, and the pathogenesis of macular edema in malignant arterial hypertension is discussed.