Non-inflammatory causes of emergency consultation in patients with multiple sclerosis.

OBJECTIVES: To describe non-relapse-related emergency consultations of patients with multiple sclerosis (MS): causes, difficulties in the diagnosis, clinical characteristics, and treatments administered. METHODS: We performed a retrospective study of patients who attended a multiple sclerosis day hospital due to suspected relapse and received an alternative diagnosis, over a 2-year period. Demographic data, clinical characteristics, final diagnosis, and treatments administered were evaluated. Patients who were initially diagnosed with pseudo-relapse and ultimately diagnosed with true relapse were evaluated specifically. As an exploratory analysis, patients who consulted with non-inflammatory causes were compared with a randomly selected cohort of patients with true relapses who attended the centre in the same period. RESULTS: The study included 50 patients (33 were women; mean age 41.4 ±â€¯11.7 years). Four patients (8%) were initially diagnosed with pseudo-relapse and later diagnosed as having a true relapse. Fever and vertigo were the main confounding factors. The non-inflammatory causes of emergency consultation were: neurological, 43.5% (20 patients); infectious, 15.2% (7); psychiatric, 10.9% (5); vertigo, 8.6% (4); trauma, 10.9% (5); and miscellaneous, 10.9% (5). CONCLUSIONS: MS-related symptoms constituted the most frequent cause of non-inflammatory emergency consultations. Close follow-up of relapse and pseudo-relapse is necessary to detect incorrect initial diagnoses, avoid unnecessary treatments, and relieve patients' symptoms.

Accelerated atherosclerosis in ANCA-associated vasculitis.

OBJECTIVES: Cardiovascular disease, including myocardial infarction and stroke, is a major cause of mortality in ANCA-associated vasculitis (AAV). Although AAV affects small vessels, an accelerated atherosclerosis not explained by traditional cardiovascular risk factors (CVRF) has been demonstrated. We aimed to investigate the association of atherosclerosis measured by carotid intima-media thickness (CIMT) and cerebral small vessel disease in AAV-patients. MATERIALS & METHODS: Twenty-three AAV-patients in complete remission were recruited. Carotid ultrasonography (US), transcranial Doppler (TCD), brain magnetic resonance imaging (MRI), and SPECT after intravenous administration of tracer 99mTc-HMPAO (dose: 720MBq) were performed. RESULTS: AAV-patients presented higher CIMT compared to normative population. Multivariate linear regression analysis demonstrated an association of higher CIMT with increased pulsatility index in middle cerebral artery (PI-MCA) (P=.011), higher lesion load on ARWMC scale (P=.011) and abnormal SPECT (P=.008). No association between higher CIMT and CVRF (diabetes or hypertension) was demonstrated. Increasing internal carotid artery pulsatility index (PI-ICA) was associated with decreasing mean flow velocity (MFV)-MCA (P=.038), increasing PI-MCA (P=.008) and increasing white matter lesions on MRI (P=.011). CONCLUSIONS: Our study adds weight to the presence of increased atherosclerosis in AAV-patients. The association observed between CIMT and PI-ICA with small vessel cerebral disease, points the possible association of easy to use carotid US in predicting microvascular brain injury.

Biological impact of cigarette smoke compared to an aerosol produced from a prototypic modified risk tobacco product on normal human bronchial epithelial cells.

Cigarette smoking causes serious and fatal diseases. The best way for smokers to avoid health risks is to quit smoking. Using modified risk tobacco products (MRTPs) may be an alternative to reduce the harm caused for those who are unwilling to quit smoking, but little is known about the toxic effects of MRTPs, nor were the molecular mechanisms of toxicity investigated in detail. The toxicity of an MRTP and the potential molecular mechanisms involved were investigated in high-content screening tests and whole genome transcriptomics analyses using human bronchial epithelial cells. The prototypic (p)MRTP that was tested had less impact than reference cigarette 3R4F on the cellular oxidative stress response and cell death pathways. Higher pMRTP aerosol extract concentrations had impact on pathways associated with the detoxification of xenobiotics and the reduction of oxidative damage. A pMRTP aerosol concentration up to 18 times higher than the 3R4F caused similar perturbation effects in biological networks and led to the perturbation of networks related to cell stress, and proliferation biology. These results may further facilitate the development of a systems toxicology-based impact assessment for use in future risk assessments in line with the 21st century toxicology paradigm, as shown here for an MRTP.

Leukoencephalopathy due to oral methotrexate.

Methotrexate (MTX) is considered the main agent for the treatment of rheumatoid arthritis (RA). Neurotoxicity is often mild, but severe encephalopathy can develop, especially with intrathecal or intravenous administration. In rare cases, this syndrome has been observed in patients on long-term low-dose oral administration. A 68-year-old male was diagnosed with RA and on treatment with oral MTX 25 mg weekly for 4 years. The patient started with progressive dysarthria, ataxia and cognitive dysfunction. Complementary tests were normal. Magnetic resonance imaging (MRI) showed hyperintense lesions in both cerebellar hemispheres on T2-weighted and FLAIR images with a diffusion restriction on diffusion-weighted imaging (DWI) and on the apparent diffusion coefficient map (ADC). On postgadolinium T1-weighted images, there were mild enhancements. Spectroscopy showed a demyelinating pattern. A pharmacogenetics determination was made, showing a heterozygous genotype in the MTHFR and ABCB1 genes. Medication with antirheumatic drug was stopped immediately on admission, and the patient gradually improved. MTX-induced leukoencephalopathy can occur even with low-dose administration. The exact pathogenic mechanism is still unknown, but it is hypothesised that it could be the result of a cumulative toxic effect on the blood-brain barrier. The nature of the relationship between the polymorphism and CNS toxicity is still unclear, and thus, further studies are warranted. Often located in the occipital lobes, the involvement of the cerebellum is quite rare. Early recognition of the condition and withdrawal of the drug lead to a better prognosis.

Crosstalk between chromatin structure, nuclear compartmentalization, and telomere biology.

Telomeres are heterochromatic structures essential for the maintenance of genomic stability and the proliferative potential of human somatic cells. A minimal length of telomeric DNA repeats and proper binding of specialized proteins are required for the maintenance of telomere structure and function. Activation of telomere length maintenance mechanisms is considered a hallmark of cancer, while attrition of telomeres is a known contributor to the phenotypes associated with the aging process. However, the molecular mechanisms responsible for telomere homeostasis are not completely understood. Compelling data indicates that the epigenetic status of telomeric and subtelomeric chromatin also plays a role in the regulation of telomere biology. In addition, genomic regions are not randomly distributed within the nucleus, but rather compartmentalized into spatial and temporal domains whose functional implications for the cell are only beginning to be unraveled. Recent studies indicate that alterations in some of the mechanisms responsible for nuclear organization associate with defects in chromatin structure. These observations suggest a link between these two processes, raising the question of whether nuclear compartmentalization of telomeres might also impact on telomere biology.

Pathogenic mechanisms for parathyroid hyperplasia.

Parathyroid hyperplasia is the cause of parathyroid gland enlargement in kidney disease (KD). Hypocalcemia, hyperphosphatemia, and vitamin D deficiency are critical contributors to the worsening of the hyperplastic parathyroid growth induced by KD. Reproduction of the features of human KD in the 5/6 nephrectomized rat model has shown that 80% of the mitogenic signals induced by KD in parathyroid cells that are aggravated by either high phosphate (P) or low calcium (Ca) diets occurred within 5 days after the onset of KD. Enhanced parathyroid expression of the potent growth promoter transforming growth factor alpha (TGFalpha) and its receptor, the epidermal growth factor receptor (EGFR), was identified as the main cause of parathyroid hyperplasia in experimental KD. Indeed, administration of highly specific EGFR-tyrosine kinase inhibitors (TKI), which block downstream signaling from TGFalpha-activated EGFR, completely prevented high P- and low Ca-induced parathyroid hyperplasia in early KD, as well as the severe progression of high P-induced parathyroid growth in established secondary hyperparathyroidism, the latter characterized by marked TGFalpha and EGFR overexpression in the parathyroid glands. More importantly, the suppression of signals downstream from TGFalpha binding to EGFR with EGFR-TKI treatment also revealed that TGFalpha self-upregulation in the parathyroid glands is the main determinant of the severity of the hyperplastic growth, and that enhanced TGFalpha activation of EGFR mediates the reduction in parathyroid vitamin D receptor levels thereby causing resistance to both the antiproliferative and parathyroid hormone-suppressive properties of calcitriol therapy.

[Regulation of the calcium-sensing receptor. Influence of secondary hyperparathyroidism]. / Regulación del receptor sensor de calcio. Influencia del hiperparatiroidismo secundario.

The parathyroid glands have a great sensitivity to small changes in the extracellular ionic calcium. The calcium-sensing receptor (CaR) is a G protein-coupled receptor that responds to extracellular ionic calcium changes activating several intracellular signalling systems (phospholipases C, A2 and D) finally inhibiting the PTH secretion. In addition to calcium, there are some other agonists and modulators such as the Mg2+, spermine, amyloid beta-peptides, a variety of aminoacids, especially aromatic aminoacids and ionic strength. In the uraemia, the sensitivity of the parathyroid glands to calcium is altered and higher values of calcium are necessary to suppress the PTH. In the secondary hyperparathyroidism the CaR expression is reduced. It has been found a negative correlation between cellular proliferation and the expression of the CaR in hyperplasic glands. Despite it is a calcium receptor, the expression of the CaR does not seem to be regulated by calcium and there is some controversy about the role of calcitriol regulating its expression. On the other hand, the phosphorous induces hyperplasia of the parathyroid gland increasing the cellular proliferation and a decrease of the CaR expression.

[Effect of desferrioxamine and deferiprone on osteocalcin secretion in osteoblast-type cells]. / Efecto de la desferrioxamina y de la deferiprona sobre la secreción de osteocalcina en células tipo osteoblasto.

Desferrioxamine and deferiprone are both metal-chelating drugs often used in aluminum-overloaded dialysis patients. In these patients, desferrioxamine produces an improvement on bone mineralisation without a relevant decrease in bone aluminum. Thus, desferrioxamine might have a direct effect on bone cells. The aim of this study was to assess the effect of desferrioxamine and deferiprone on 1,25(OH)2D3-stimulated osteocalcin secretion in osteoblast--like cells. The study was carried out in MG-63 cell cultures. Cells were seeded at a density of 15,000 cel/cm2 and grown to confluence for 72 hours in DMEM supplemented with 10% FCS. The medium was then replaced by another medium containing 1% BSA, 10(-9) M 1,25(OH)2D3 and desferrioxamine 5, 10, 20, 40, 60, 80 microM or deferiprone 15, 30, 60, 120, 180, 240 microM. Tris-HCl at pH 7.4 was used as control. After 48 hours, supernatants were collected for the measurement of secreted osteocalcin. Desferrioxamine and deferiprone, at high doses (desferrioxamine: 60 microM, 80 microM; deferiprone: 180 microM, 240 microM), inhibited the 1,25(OH)2D3-induced osteocalcin secretion. On the contrary, at lower doses (desferrioxamine 5 microM; deferiprone 15 microM) stimulated the secretion. In summary, these results suggest that desferrioxamine and deferiprone exert a direct effect on bone cell metabolism that might be independent from their metal-chelating properties.