Brain parenchymal damage in neuromyelitis optica spectrum disorder - A multimodal MRI study.

OBJECTIVE: To investigate different brain regions for grey (GM) and white matter (WM) damage in a well-defined cohort of neuromyelitis optica spectrum disorder (NMOSD) patients and compare advanced MRI techniques (VBM, Subcortical and cortical analyses (Freesurfer), and DTI) for their ability to detect damage in NMOSD. METHODS: We analyzed 21 NMOSD patients and 21 age and gender matched control subjects. VBM (GW/WM) and DTI whole brain (TBSS) analyses were performed at different statistical thresholds to reflect different statistical approaches in previous studies. In an automated atlas-based approach, Freesurfer and DTI results were compared between NMOSD and controls. RESULTS: DTI TBSS and DTI atlas based analysis demonstrated microstructural impairment only within the optic radiation or in regions associated with the optic radiation (posterior thalamic radiation p < 0.001, 6.9 % reduction of fractional anisotropy). VBM demonstrated widespread brain GM and WM reduction, but only at exploratory statistical thresholds, with no differences remaining after correction for multiple comparisons. Freesurfer analysis demonstrated no group differences. CONCLUSION: NMOSD specific parenchymal brain damage is predominantly located in the optic radiation, likely due to a secondary degeneration caused by ON. In comparison, DTI appears to be the most reliable and sensitive technique for brain damage detection in NMOSD. KEY POINTS: • The hypothesis of a widespread brain damage in NMOSD is challenged. • The optic radiation (OR) is the most severely affected region. • OR-affection is likely due to secondary degeneration following optic neuritis. • DTI is currently the most sensitive technique for NMOSD-related brain-damage detection. • DTI is currently the most reliable technique for NMOSD-related brain-damage detection.

Altered basal ganglia functional connectivity in multiple sclerosis patients with fatigue.

BACKGROUND: Fatigue is one of the most frequent and disabling symptoms in multiple sclerosis, but its pathophysiological mechanisms are poorly understood. It is in particular unclear whether and how fatigue relates to structural and functional brain changes. OBJECTIVE: We aimed to analyse the association of fatigue severity with basal ganglia functional connectivity, basal ganglia volumes, white matter integrity and grey matter density. METHODS: In 44 patients with relapsing-remitting multiple sclerosis and 20 age- and gender-matched healthy controls, resting-state fMRI, diffusion tensor imaging and voxel-based morphometry was performed. RESULTS: In comparison with healthy controls, patients showed alteration of grey matter density, white matter integrity, basal ganglia volumes and basal ganglia functional connectivity. No association of fatigue severity with grey matter density, white matter integrity and basal ganglia volumes was observed within patients. In contrast, fatigue severity was negatively correlated with functional connectivity of basal ganglia nuclei with medial prefrontal cortex, precuneus and posterior cingulate cortex in patients. Furthermore, fatigue severity was positively correlated with functional connectivity between caudate nucleus and motor cortex. CONCLUSION: Fatigue is associated with distinct alterations of basal ganglia functional connectivity independent of overall disability. The pattern of connectivity changes suggests that disruption of motor and non-motor basal ganglia functions, including motivation and reward processing, contributes to fatigue pathophysiology in multiple sclerosis.

Lymphoid cell-glioma cell interaction enhances cell coat production by human gliomas: novel suppressor mechanism.

Certain human glioma lines produce mucopolysaccharide coats that impair the generation of cytolytic lymphocytes in response to these lines in vitro. Coat production is substantially enhanced by the interaction of glioma cells with a macromolecular factor released by human peripheral blood mononuclear cells in culture. This interaction thus constitutes an unusual mechanism by which inflammatory cells may nonspecifically suppress the cellular immune response to at least one class of solid tumors in humans.

Algebraic Helmholtz inversion in planar magnetic resonance elastography.

Magnetic resonance elastography (MRE) is an increasingly used noninvasive modality for diagnosing diseases using the response of soft tissue to harmonic shear waves. We present a study on the algebraic Helmholtz inversion (AHI) applied to planar MRE, demonstrating that the deduced phase speed of shear waves depends strongly on the relative orientations of actuator polarization, motion encoding direction and image plane as well as on the actuator plate size, signal-to-noise ratio and discretization of the wave image. Results from the numerical calculation of harmonic elastic waves due to different excitation directions and simulated plate sizes are compared to experiments on a gel phantom. The results suggest that correct phase speed can be obtained despite these largely uncontrollable influences, if AHI is based on out-of-plane displacements and the actuator is driven at an optimal frequency yielding an optimal pixel per wavelength resolution in the wave image. Assuming plane waves, the required number of pixels per wavelength depends only on the degree of noise.

Horizontal shear wave scattering from a nonwelded interface observed by magnetic resonance elastography.

A method based on magnetic resonance elastography is presented that allows measuring the weldedness of interfaces between soft tissue layers. The technique exploits the dependence of shear wave scattering at elastic interfaces on the frequency of vibration. Experiments were performed on gel phantoms including differently welded interfaces. Plane wave excitation parallel to the planar interface with corresponding motion sensitization enabled the observation of only shear-horizontal (SH) wave scattering. Spatio-temporal filtering was applied to calculate scattering coefficients from the amplitudes of the incident, transmitted and reflected SH-waves in the vicinity of the interface. The results illustrate that acoustic wave scattering in soft tissues is largely dependent on the connectivity of interfaces, which is potentially interesting for imaging tissue mechanics in medicine and biology.

Three-dimensional analysis of shear wave propagation observed by in vivo magnetic resonance elastography of the brain.

Dynamic magnetic resonance elastography (MRE) is a non-invasive method for the quantitative determination of the mechanical properties of soft tissues in vivo. In MRE, shear waves are generated in the tissue and visualized using phase-sensitive MR imaging methods. The resulting two-dimensional (2-D) wave images can reveal in-plane elastic properties when possible geometrical biases of the wave patterns are taken into account. In this study, 3-D MRE experiments of in vivo human brain are analyzed to gain knowledge about the direction of wave propagation and to deduce in-plane elastic properties. The direction of wave propagation was determined using a new algorithm which identifies minimal wave velocities along rays from the surface into the brain. It was possible to quantify biases of the elastic parameters due to projections onto coronal, sagittal and transversal image planes in 2-D MRE. It was found that the in-plane shear modulus is increasingly overestimated when the image slice is displaced from narrow slabs of 2-5cm through the center of the brain. The mean shear modulus of the brain was deduced from 4-D wave data with about 3.5kPa. Using the proposed slice positions in 2-D MRE, this shear modulus can be reproduced with an acceptable error within a fraction of the full 3-D examination time.

Dietary factors in relation to rheumatoid arthritis: a role for olive oil and cooked vegetables?

BACKGROUND: Although several studies showed that risk of rheumatoid arthritis (RA) is inversely associated with consumption of n-3 fatty acids, the one study showing that olive oil may have a protective role has not yet been confirmed. OBJECTIVE: We examined the relation between dietary factors and risk of RA in persons from southern Greece. DESIGN: We studied 145 RA patients and 188 control subjects who provided information on demographic and socioeconomic variables, prior medical and family history, and present disease status. Subjects responded to an interviewer-administered, validated, food-frequency questionnaire that assessed the consumption of >100 food items. We calculated chi-square statistics for linear trend and odds ratios (ORs) for the development of RA in relation to the consumption of olive oil, fish, vegetables, and a series of food groups classified in quartiles. RESULTS: Risk of developing RA was inversely and significantly associated only with cooked vegetables (OR: 0.39) and olive oil (OR: 0.39) by univariate analysis. A significant trend was observed with increasing olive oil (chi-square: 4.28; P = 0.03) and cooked vegetable (chi-square: 10. 48; P = 0.001) consumption. Multiple logistic regression analysis models confirmed the independent and inverse association between olive oil or cooked vegetable consumption and risk of RA (OR: 0.38 and 0.24, respectively). CONCLUSIONS: Consumption of both cooked vegetables and olive oil was inversely and independently associated with risk of RA in this population. Further research is needed to elucidate the underlying mechanisms of this finding, which may include the antioxidant properties or the high n-9 fatty acid content of the olive oil.

A crossover clinical trial of piroxicam, indomethacin and ibuprofen in rheumatoid arthritis.

A single-blind, crossover trial was carried out in 24 patients with definite or classical rheumatoid arthritis to compare the effectiveness and tolerability of piroxicam (20 mg once daily) with that of indomethacin (25 mg 3-times daily), ibuprofen (400 mg 3-times daily) and placebo. Each drug was given in random order for a period of 1 week. Pain, joint tenderness and morning stiffness decreased and grip strength increased with piroxicam compared to placebo; no statistically significant difference could be found between piroxicam and the two other active agents. A reduction in joint circumference could not be demonstrated with piroxicam or ibuprofen but most patients did not have reducible swelling in their finger joints. Piroxicam was just as effective as the other two drugs overall, but fewer side-effects were noted with piroxicam.

Primary polymorphous hemangioendothelioma of the spinal cord. Case report.

A case of polymorphous hemangioendothelioma of the spinal cord is described. This 55-year-old woman presented with an 18-month history of lower-extremity sensorimotor deficit. A magnetic resonance image revealed an enhancing, intradural, extramedullary nodule at the T 1-2 level. On gross inspection, the lesion measured 3.5 cm and was firmly attached to spinal cord parenchyma and adjacent nerve roots. It was completely removed. Fourteen months after surgery the patient's neurological deficit had resolved. Polymorphous hemangioendothelioma is a rare vascular tumor of borderline malignancy. Most occur in lymph nodes. None has been reported to occur in the central and peripheral nervous system. Based on current experience, resection and close follow up seems the best therapeutic approach.

Plasma renin activity as a marker of renovascular injury in patients with rheumatoid arthritis.

OBJECTIVES: To assess whether plasma renin activity (PRA) in patients with rheumatoid arthritis (RA) and evidence of renal involvement (microhematuria) can serve as potential marker of renovascular injury. METHODS: PRA was measured at rest and following exercise. All nonsteroidal antiinflammatory drugs or other medications that might affect renin release were stopped at least ten days prior to PRA measurements. PRA was correlated with the number of dysmorphic erythrocytes present in the urine sediment as indicators of glomerular capillary injury (microhematuria). RESULTS: All patients with RA had a higher mean PRA than controls. Moreover, all patients with RA in whom microhematuria was present had a higher PRA than those without microhematuria. Simple and multiple regression analysis revealed a significant correlation between: a) PRA and rheumatoid factor levels; b) rheumatoid factor levels and the number of erythrocytes in the urine sediment; and c) PRA levels and the number of erythrocytes in the urine sediment. CONCLUSIONS: The observations indicate that increased PRA may occur in normotensive patients with RA and no clinical or biochemical evidence of renal involvement. This may reflect activation of the renin-angiotensin system. The positive correlation between enhanced PRA, rheumatoid factor levels and microhematuria in RA patients may indicate inflammatory injury of the glomerular microvasculature involving the juxtaglomerular apparatus.

Cold-induced coronary Raynaud's phenomenon in patients with systemic sclerosis.

OBJECTIVE: Cardiac involvement with myocardial-band necrosis is common in systemic sclerosis. One possible explanation is that an underlying vasomotor abnormality accounts for these histologic findings. To shed light on this issue we investigated the existence of "myocardial Raynaud's phenomenon" in such patients. METHODS: We examined 25 patients with systemic sclerosis and 14 patients with systemic lupus erythematosus or rheumatoid arthritis, using cold pressor and dipyridamole-thallium-201 scintigraphy. RESULTS: Twenty-three patients with systemic sclerosis and 13 patients with lupus erythematosus or rheumatoid arthritis had normal perfusion during dipyridamole imaging. Seven scleroderma patients with normal dipyridamole test presented cold-induced transient myocardial ischemia, while none of the control patients had cold-induced ischemia (p = 0.034). All patients with cold-induced ischemic defects presented long-standing Raynaud's phenomenon (> 5 years); of the 14 patients with long-standing Raynaud's phenomenon 7 presented ischemic thallium-201 defects; of the remaining 9 patients with Raynaud's phenomenon of short duration (< 5 years) none presented cold-induced ischemia (p = 0.019). CONCLUSION: Patients with systemic sclerosis and long-standing Raynaud's phenomenon, even in the presence of normal myocardial perfusion during pharmacological vasodilation with dipyridamole, may present cold-induced myocardial ischemia, a functional Raynaud's phenomenon of the heart.

Serum vitamin B12 and folic acid levels in hyperthyroidism.

Serum vitamin B12 and folic acid levels were measured in 48 hyperthyroid patients and in a group of euthyroid controls. The levels of vitamin B12 ranged from 120-900 pg/ml with a mean of 429.3 +/- 30.9 pg/ml (SE). The mean serum vitamin B12 level was lower in hyperthyroid patients than in normal controls, the difference being statistically significant (t = 2.584, p less than 0.025). Serum vitamin B12 levels showed a statistically significant negative correlation with the clinical index of Grooks et al. (r = 0.344, p less than 0.05). The findings, although not excluding the involvement of auto-immune gastritis in patients with low serum vitamin B12 levels, suggest a direct action of increased thyroid hormone concentrations. Serum folic acid levels ranged from 0.5-13.8 ng/ml with a mean of 6.8 +/- 0.46 ng/ml (SE). The mean serum folic acid levels were higher in the hyperthyroid patients than in normal controls but the difference was not statistically significant (t = 1.2, p greater than 0.2). The serum folic acid levels did not show any statistically significant correlation with the clinical index of Grooks et al. The fact that no statistically significant difference was found between the mean value in hyperthyroid patients and the mean value in normal controls is probably due to the high folic acid intake in Greece.

Determinants of exercise-induced ST segment depression in patients with coronary artery disease: a multivariate approach.

The purpose of this study was to delineate among the usually gathered parameters in an electrocardiographic exercise test the determinants of its positive outcome (delta ST decreases > or = 1 mm measured at 80 msec from the J point). The authors studied 832 patients investigated with Bruce's exercise testing and with diagnostic coronary arteriography, all of whom were shown to have significant coronary artery disease (diameter stenosis > or = 50%). Twenty-five demographic, clinical, electrocardiographic, exercise, and anatomic/hemodynamic parameters were analyzed. The stepwise forward logistic regression analysis retained seven among them as significant independent predictors: four as positive contributors: (1) three-vessel and/or left main disease (P = 0.0000), (2) Gensini's angio-graphic score for disease extent (P = 0.0025), (3) anginal pain during the test (P = 0.0000), and (4) age (P = 0.0031) and three as negative contributors: (1) resting heart rate (P = 0.0004), (2) history of old myocardial infarction (P = 0.0019), and (3) pathological Q waves at the resting ECG (P = 0.0018). These findings establish standards that permit the prediction of the positive electrocardiographic exercise outcome in patients with significant coronary disease.

Increased biosynthesis of complement components by cultured monocytes, synovial fluid macrophages and skynovial membrane cells from patients with rheumatoid arthritis.

Monocytes, synovial fluid (SF) and synovial membrane (SM) macrophages from patients with rheumatoid arthritis (RA) were maintained in short-term tissue culture for up to 10 days, and the synthesis of C4, C2, C3, C5, factor B(B), D, properdin (P), C3b inactivator (C3bINA) and beta 1H globulin studied. Functionally active C2, B, D, P, C3bINA and beta 1H were synthesized by the cells in each type of culture. C4, C3 and C5 could be detected, but were functionally inactive. RA monocytes synthesized more C2 than monocytes from patients with degenerative joint disease (DJD) (P < 0.001). Similar studies revealed that SF macrophages synthesized more C3 than SM macrophages (P < 0.001) which in turn produced more C2 than monocytes (P < 0.001). Other experiments showed that SF macrophages synthesized more of each component than the other cell types. SM macrophages made more C2 than B than RA and DJD monocytes, but synthesized only small quantities of P, D and beta 1H. RA monocytes synthesized more of each component than DJD monocytes. The results of these studies show that (1) in RA, complement components can be synthesized locally in the inflamed joints, and (2) local factors in the joints probably stimulate complement synthesis.

Late occurrence of malignancy in a ganglioneuroma 19 years following radiation therapy to a neuroblastoma.

Neuroblastoma is a common solid tumor of childhood. Maturation to a ganglioneuroma or regression has been reported to occur spontaneously or following minimal treatment. Malignant degeneration of such a ganglioneuroma is extremely rare. We present a report of a malignant tumor arising in a ganglioneuroma 19 years following abdominal radiation therapy for neuroblastoma.

Retinal toxicity in long term hydroxychloroquine treatment.

OBJECTIVE: To report clinical experience from patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) who were receiving recommended doses of hydroxychloroquine for more than six years, and were monitored for evidence of hydroxychloroquine related retinopathy every six months. METHODS: A prospective (and continuing) evaluation was made of the potential retinal toxicity of hydroxychloroquine in a cohort of 360 Greek patients followed for RA and SLE, 58 of whom have received long term treatment ( > six years). Fundoscopy, colour vision tests, dark adaptation tests, visual field testing, automated perimetry, and electroretinogram were performed every six months. RESULTS: Among 58 patients receiving hydroxychloroquine for more than six years, two relatively young women (3.5%), one treated for RA and the other treated for SLE, developed characteristic hydroxychloroquine related toxic retinal lesions after cumulative doses of 700 g (6.5 years) and 730 g (8 years) of hydroxychloroquine, respectively. Bilateral visual acuity was 6/6 and 6/7.5, respectively; both patients had normal colour perception. Despite an early diagnosis and cessation of treatment, permanent visual field paracentral scotomata in both patients, and persisting lesions in fluorescein angiography in the patient with SLE, were observed at 4.5 and 3 years of follow up, respectively. No other specific cases of hydroxychloroquine related retinopathy have to date been identified in the remaining 302 patients. CONCLUSION: Cases of irreversible, hydroxychloroquine related retinopathy in patients who did not receive overdoses have not been reported previously. The present observations in two relatively young patients should raise our concern regarding the long term usage of an increasingly popular medication in rheumatology practice.

Diffusing capacity of the lung and nifedipine in systemic sclerosis.

Lung involvement in systemic sclerosis may be due in part to a functional abnormality of the pulmonary vasculature. To investigate the possible role of a pulmonary vasospastic process in this disorder, 21 non-smoking patients who had no evidence of cardiac disease or pulmonary hypertension were evaluated with pulmonary function tests prior to administration of nifedipine, 30 minutes after a single oral dose of nifedipine (20 mg), and after 4 weeks of treatment with nifedipine (10 mg 3 times daily). Treatment with nifedipine did not significantly change any of the pulmonary function values, except for the carbon monoxide diffusing capacity (DLCO). The linear trend between the individual DLCO values at baseline and their changes immediately following the initial 20-mg dose of nifedipine (r = -0.603, P = 0.02) and after 4 weeks of treatment (r = -0.636, P = 0.01) showed that the lower the DLCO value at baseline, the greater the improvement caused by nifedipine. These findings support the hypothesis of a potentially reversible pulmonary vasospasm in systemic sclerosis and suggest that nifedipine may be useful in the treatment of lung disease in these patients; however, further studies are needed.

Radiological manifestations in 200 patients with ankylosing spondylitis: correlation with clinical features and HLA B27.

The radiological manifestations of 200 patients with ankylosing spondylitis were appraised, and correlated with the patient's sex, anterior uveitis, and HLA B27. Radiological findings in female patients were no different from male patients. Only syndesmophyte formation in the spine was found significantly more frequently in patients with uveitis and HLA B27. Osteoporosis of the spine correlated strongly with a later age of onset, longer duration of the disease, older age at the time of study, Romanus lesions, syndesmophytes, spinal fusion, osteitis pubis, and widespread radiological destructive peripheral joint disease. Syndesmophytes were most frequently present at the dorso-lumbar junction. Spondylodiscitis was present in 8 patients and was most commonly present in the thoracic spine.