Prevalence of primary headaches in multiple sclerosis patients.

BACKGROUND: Multiple sclerosis (MS) is the most common immune-mediated inflammatory disease of the central nervous system. It is characterized by symptoms such as visual disturbances, paresis with spasticity, paresthesia, numbness, and fatigue. However, several studies have shown a high prevalence of headaches in individuals with MS. Migraine and tension-type headaches are the most frequent types of headaches experienced by those with MS. Additionally, the role of MS disease-modifying agents must be considered. These agents have different modes of action and side effect profiles, and their use may sometimes trigger headaches in patients with MS. OBJECTIVES: This study aimed to explore the prevalence and clinical characteristics of primary headaches in MS patients. The relationship between headache and clinical features of MS (Course of MS, duration, EDSS, brain imaging and DMD) are also investigated. SUBJECTS AND METHODS: Two hundred and eighty-one MS patients diagnosed according to according to the 2017 revisions to the McDonald Criteria were included in the study. Data was collected from the MS unit medical records and from the interview with the patients. Patients with reported headaches are asked to recall their headache characteristics and patterns using an interviewer administered Arabic language-structured validated questionnaire. RESULTS: The median age of patients was 33 years old, with a range of 22-55. Tension-type headache (TTH) was more common in males, patients with more severe disability (EDSS ≥ 3), and those with SPMS and PPMS phenotypes. Additionally, patients on rituximab or cyclophosphamide therapy were more likely to have TTH. On the other hand, females, patients with milder disability (EDSS < 3), and those with RRMS phenotype were more likely to have migraine. This was also true for patients with MRI lesions involving the periaqueductal gray, and those receiving INF or fingolimod (P < 0.05). Periaqueductal gray matter lesions were found in the MRI of 48 patients (40 %) who experienced headaches on more than 10 days per month. Sensorimotor lesions in the brain were found in 55 patients (53.4 %) with severe headaches (p-value < 0.001). Interferons were associated with an increased risk of worsening preexisting headaches and the appearance of de novo headaches related to its intake (odds ratio: 2.84, 3.72; relative risk: 1.63, 2.04; p-value = 0.03, < 0.001, respectively). On the other hand, rituximab was associated with a decreased risk of worsening preexisting headaches and the appearance of de novo headaches related to its intake (odds ratio: 0.04, 0.09; relative risk: 0.11, 0.18; p-value = < 0.001, < 0.001, respectively). CONCLUSION: Primary headaches are a common occurrence in patients with MS. Migraines and tension-type headaches (TTH) are among the most prevalent types. It has been observed that interferon can exacerbate preexisting headaches and even cause new ones. Additionally, the location of MS plaques may play a role in the frequency and severity of headaches.

Role of micro-RNA132 and its long non coding SOX2 in diagnosis of lupus nephritis.

BACKGROUND: The skin and the kidney are commonly affected in systemic lupus erythematosus (SLE) with similar molecular mechanisms. Although clinical indicators of renal injury in SLE are fairly uncontroversial, few biomarkers are reliable. The role of micro-RNAs (mi-RNAs) in lupus nephritis (LN) pathogenesis has been investigated to help in early diagnosis. PURPOSE: The aim of work is to evaluate miRNA132 and SOX2 expressions in SLE Egyptian patients; with and without nephritis, and the relation between miRNA132 and its long non-coding gene SOX2 in both patients groups. RESEARCH DESIGN: This is a case-control study involving 100 SLE patients with and without LN (LN and non-LN groups), and 50 age-and sex-matched healthy controls. The study was carried out to detect miRNA132 and SOX2 expression by quantitative Real-Time Polymerase chain reaction methods. The SLE disease activity index (SLEDAI) was assessed. RESULTS: SLEDAI increased in LN compared to non-LN. Micro-RNA132 expression was significantly increased in patient groups compared to controls (p<0.01) and increased in LN more than non-LN group (p<0.001). SOX2 significantly decreased in patient groups compared to controls (p<0.001), and was more in LN compared to non-LN group (p<0.001). There was a negative correlation between miRNA132 and SOX2 expression in both patient groups (p<0.001). CONCLUSION: miRNA132 and SOX2 may play a role in SLE activity and help in the early non-invasive diagnosis of LN.

Effect of histone deacetylase inhibitor on epithelial-mesenchymal transition of liver fibrosis.

Liver fibrosis is an excessively reversible wound healing process and the fibrotic disorder is the activation of hepatic stellate cell that requires extensive alterations in gene expression. As reversible deacetylation of histone proteins modulate gene expression, we examined the effect of valproic acid (VPA) as selective histone deacetylase inhibitor on CCl-4 induced liver fibrosis. Thirty rats were divided into three equal groups; control group, fibrotic group and VPA-treated group. The rats were sacrificed after 6 weeks of liver fibrosis induction. The histopathological effect on liver tissue was examined. The expression of α-SMA and Smad-4 mRNA and serum levels of TGF-ß1, alanine aminotransferase, and aspartate aminotransferase were determined. Treatment of rats with VPA attenuated carbon tetrachloride-induced liver fibrosis. Moreover, α-SMA and Smad-4 expression was repressed under VPA treatment and both serum TGF-ß1 and liver enzymes were significantly decreased. The histone deacetylase inhibitor-1 VPA inhibits the epithelial-mesenchymal transition and affects hepatic stellate cell activation during liver fibrosis through downregulation of Smad4 and α-SMA expression which may serve as a promising agent in liver fibrosis treatment. © 2018 IUBMB Life, 70(6):511-518, 2018.

Analysis of the catalytic and binding residues of the diadenosine tetraphosphate pyrophosphohydrolase from Caenorhabditis elegans by site-directed mutagenesis.

The contributions to substrate binding and catalysis of 13 amino acid residues of the Caenorhabditis elegans diadenosine tetraphosphate pyrophosphohydrolase (Ap(4)A hydrolase) predicted from the crystal structure of an enzyme-inhibitor complex have been investigated by site-directed mutagenesis. Sixteen glutathione S-transferase-Ap(4)A hydrolase fusion proteins were expressed and their k(cat) and K(m) values determined after removal of the glutathione S-transferase domain. As expected for a Nudix hydrolase, the wild type k(cat) of 23 s(-1) was reduced by 10(5)-, 10(3)-, and 30-fold, respectively, by replacement of the conserved P(4)-phosphate-binding catalytic residues Glu(56), Glu(52), and Glu(103) by Gln. K(m) values were not affected, indicating a lack of importance for substrate binding. In contrast, mutating His(31) to Val or Ala and Lys(83) to Met produced 10- and 16-fold increases in K(m) compared with the wild type value of 8.8 microm. These residues stabilize the P(1)-phosphate. H31V and H31A had a normal k(cat) but K83M showed a 37-fold reduction in k(cat). Lys(36) also stabilizes the P(1)-phosphate and a K36M mutant had a 10-fold reduced k(cat) but a relatively normal K(m). Thus both Lys(36) and Lys(83) may play a role in catalysis. The previously suggested roles of Tyr(27), His(38), Lys(79), and Lys(81) in stabilizing the P(2) and P(3)-phosphates were not confirmed by mutagenesis, indicating the absence of phosphate-specific binding contacts in this region. Also, mutating both Tyr(76) and Tyr(121), which clamp one substrate adenosine moiety between them in the crystal structure, to Ala only increased K(m) 4-fold. It is concluded that interactions with the P(1)- and P(4)-phosphates are minimum and sufficient requirements for substrate binding by this class of enzyme, indicating that it may have a much wider substrate range then previously believed.

The crystal structure of diadenosine tetraphosphate hydrolase from Caenorhabditis elegans in free and binary complex forms.

The crystal structure of C. elegans Ap(4)A hydrolase has been determined for the free enzyme and a binary complex at 2.0 A and 1.8 A, respectively. Ap(4)A hydrolase has a key role in regulating the intracellular Ap(4)A levels and hence potentially the cellular response to metabolic stress and/or differentiation and apoptosis via the Ap(3)A/Ap(4)A ratio. The structures reveal that the enzyme has the mixed alpha/beta fold of the Nudix family and also show how the enzyme binds and locates its substrate with respect to the catalytic machinery of the Nudix motif. These results suggest how the enzyme can catalyze the hydrolysis of a range of related dinucleoside tetraphosphate, but not triphosphate, compounds through precise orientation of key elements of the substrate.

Crystallization of a complex of Caenorhabditis elegans diadenosine tetraphosphate hydrolase and a non-hydrolysable substrate analogue, AppCH2ppA.

The molecule diadenosine tetraphosphate (Ap(4)A) has been suggested to be a component of the cellular response to metabolic stress and/or, via the intracellular Ap(3)A/Ap(4)A ratio, to be involved in differentiation and apoptosis. Thus, the enzyme Ap(4)A hydrolase has a key metabolic role through regulation of the intracellular Ap(4)A levels. Crystals of this enzyme from the nematode Caenorhabditis elegans have been obtained in the presence of a non-hydrolysable substrate analogue, AppCH(2)ppA. The crystals belong to space group P2(1), unit-cell parameters a = 57.6, b = 36.8, c = 68.9 A, beta = 114.2 degrees, and diffract to approximately 2.0 A. Determination of the structure of this complex will provide insights into the substrate specificity and catalytic activity of this class of enzymes.