Mapping of MRX81 in Xp11.2-Xq12 suggests the presence of a new gene involved in nonspecific X-linked mental retardation

X-linked nonspecific mental retardation (MRX) accounts for approximately 25% of mental retardation in males. A number of MRX loci have been mapped on the X chromosome, reflecting the complexity of gene action in central nervous system (CNS) specification and function. Eleven MRX genes have been identified, but many other causative loci remain to be refined to the single gene level. In 21 MRX families, the causative gene is located in the pericentromeric region; and we report here the identification by linkage analysis of a further such locus, MRX81. The new MRX locus was identified by two- and multi-point parametric analysis carried out on a large Italian family. Tight linkage of MRX81 to DNA markers ALAS2, DXS991, and DXS7132 was observed with a maximum LOD score of 3.43. Haplotype construction delineates an MRX81 critical region of 8 cM, the smallest MRX pericentromeric interval so far described, between DXS1039 and DXS1216, and placing it in Xp11.2-Xq12. So far, automated sequencing of two candidates in the region, the MRX gene oligophrenin (OPHN1) and the brain-specific ephrinB1 (EFNB1) gene, in DNA from affected males excluded their candidacy for MRX81, suggesting a novel disease gene.     

Signaling events involved in cytokine and chemokine production induced by secretory phospholipase A2 in human lung macrophages

Secretory phospholipases A(2) (sPLA(2)) are enzymes released during inflammatory reactions. These molecules activate immune cells by mechanisms either related or unrelated to their enzymatic activity. We examined the signaling events activated by group IA (GIA) and group IB (GIB) sPLA(2) in human lung macrophages leading to cytokine/chemokine production. sPLA(2) induced the production of cytokines (TNF-alpha, IL-6 and IL-10) and chemokines (CCL2, CCL3, CCL4 and CXCL8), whereas no effect was observed on IL-12, CCL1, CCL5 and CCL22. sPLA(2) induced the phosphorylation of the MAPK p38 and ERK1/2, and inhibition of these kinases by SB203580 and PD98059, respectively, reduced TNF-alpha and CXCL8 release. Suppression of sPLA(2) enzymatic activity by a site-directed inhibitor influenced neither cytokine/chemokine production nor activation of MAPK, whereas alteration of sPLA(2) secondary structure suppressed both responses. GIA activated the phosphatidylinositol 3-kinase (PI3 K)/Akt system and a specific inhibitor of PI3 K (LY294002) reduced sPLA(2)-induced release of TNF-alpha and CXCL8. GIA promoted phosphorylation and degradation of IkappaB and inhibition of NF-kappaB by MG-132 and 6-amino-4-phenoxyphenylethylamino-quinazoline suppressed the production of TNF-alpha and CXCL8. These results indicate that sPLA(2) induce the production of cytokines and chemokines in human macrophages by a non-enzymatic mechanism involving the PI3 K/Akt system, the MAPK p38 and ERK1/2 and NF-kappaB.     

Multistep, sequential control of the trafficking and function of the multiple sulfatase deficiency gene product, SUMF1 by PDI, ERGIC-53 and ERp44

Sulfatase modifying factor 1 (SUMF1) encodes for the formylglicine generating enzyme, which activates sulfatases by modifying a key cysteine residue within their catalytic domains. SUMF1 is mutated in patients affected by multiple sulfatase deficiency, a rare recessive disorder in which all sulfatase activities are impaired. Despite the absence of canonical retention/retrieval signals, SUMF1 is largely retained in the endoplasmic reticulum (ER), where it exerts its enzymatic activity on nascent sulfatases. Part of SUMF1 is secreted and paracrinally taken up by distant cells. Here we show that SUMF1 interacts with protein disulfide isomerase (PDI) and ERp44, two thioredoxin family members residing in the early secretory pathway, and with ERGIC-53, a lectin that shuttles between the ER and the Golgi. Functional assays reveal that these interactions are crucial for controlling SUMF1 traffic and function. PDI couples SUMF1 retention and activation in the ER. ERGIC-53 and ERp44 act downstream, favoring SUMF1 export from and retrieval to the ER, respectively. Silencing ERGIC-53 causes proteasomal degradation of SUMF1, while down-regulating ERp44 promotes its secretion. When over-expressed, each of three interactors favors intracellular accumulation. Our results reveal a multistep control of SUMF1 trafficking, with sequential interactions dynamically determining ER localization, activity and secretion.     

Pentraxin 3 (PTX3) inhibits plasma cell/stromal cell cross‐talk in the bone marrow of multiple myeloma patients

Pentraxin 3 (PTX3) is a soluble pattern recognition receptor that binds with high affinity and selectivity to fibroblast growth factor‐2 (FGF2), thus inhibiting its pro‐angiogenic activity. Here we investigated the effects of PTX3 on monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) patient‐derived bone marrow (BM) plasma cells (PCs), endothelial cells (ECs), and fibroblasts (FBs), and assessed whether PTX3 can modulate the cross‐talk between PCs and those microenvironment cells. PTX3 and FGF2 expression was evaluated by ELISA. Functional studies, including cell viability, wound healing, chemotaxis, and Matrigel^® assays, were performed on MGUS and MM ECs and FBs upon the PTX3 treatment. Through western blot PTX3‐induced modulation in FGF2/FGF receptor signalling pathways was evaluated in MGUS and MM ECs and FBs through western blot. Co‐cultures between MM ECs/FBs and human PC lines were used to evaluate possible PTX3 indirect effects on MM PCs. Adhesion molecules were studied by flow cytometry. PTX3 provides a direct time‐ and dose‐dependent apoptotic effect on MM ECs and FBs, but not on either MM primary PCs or human PC lines. PTX3 inhibits migration of MM ECs and FBs in a dose‐dependent manner, and impacts in vitro and in vivo FGF2‐mediated MM angiogenesis. Co‐cultures of PCs and ECs/FBs show that PTX3 treatment indirectly impairs PC viability and adhesion. We conclude that PTX3 is an anti‐angiogenic factor in MM and behaves as a cytotoxic molecule on MM cells by inhibiting the cross‐talk between PCs and ECs/FBs. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Co-expression of Epstein-Barr virus latent membrane protein and vimentin in “aggressive” histological subtypes of Hodgkin's disease

Summary The presence of Epstein-Barr virus (EBV) genome in Hodgkin's and Reed-Sternberg (HRS) cells, as detected using in situ hybridization (ISH) with biotinylatedBamHI V probes, along with the expression of EBV-encoded latent membrane protein (LMP) and vimentin was examined in paraffin-embedded sections of 39 immunomorphologically characterized cases of Hodgkin's disease (HD). ISH demonstrated EBV in HRS cells in 15 of 39 cases, whereas LMP expression was detected in 11 of 39 cases, only in the presence of EBV genome detection. With the exception of 1 case, in which HRS cells expressed B-cell-associated antigens, the LMP-positive cases included specimens in which HRS cells were of non-B, non-T phenotype. LMP expression showed a stronger association with lymphocyte depletion (LD) (3/3) and mixed cellularity (MC) (6/11) than with lymphocyte predominance (0/5) or nodular sclerosis (2/20) subtypes. Vimentin expression on HRS cells was found in all the LMP-expressing cases and only in a fraction (13/28) of LMP-negative cases. This study supports the view that HD represents a heterogeneous group of diseases also in terms of EBV association, LMP expression being strongly related to the aggressive LD and MC histological subtypes. In light of the supposed interactions between vimentin and LMP, their coexpression on HRS cells, as detected in this study, provides further evidence for a significant role of EBV in the development of a proportion of HD cases.     

Clinical features of Sjogren’s syndrome in patients with multiple sclerosis

Annunziata P, De Santi L, Di Rezze S, Millefiorini E, Capello E, Mancardi G, De Riz M, Scarpini E, Vecchio R, Patti F. Clinical features of Sjogren’s syndrome in patients with multiple sclerosis.
Acta Neurol Scand: 2011: 124: 109–114.
© 2010 John Wiley & Sons A/S. Objectives – To assess the frequency of clinical features of Sjogren’s syndrome (SS) in patients with multiple sclerosis (MS) receiving treatment with disease‐modifying drugs (DMDs) or naïve to treatment and the possible association with clinical, cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) parameters. Methods – A multicentre cross‐sectional observational study was designed, based on a structured neurologist‐administered questionnaire to 440 patients. Results – Twenty‐eight of 230 (12%) patients receiving treatment with DMDs (DMDs⁺) and 14 of 210 (6.6%) treatment‐naïve patients (DMDs⁻) showed clinical features of SS. Four primary SS were diagnosed, two of which were DMDs⁺ and two were DMDs⁻. Sicca symptoms were significantly associated with higher EDSS scores (P = 0.018), a low frequency of gadolinium‐enhanced MRI‐positive lesions (P = 0.018) and cerebral disturbances (P = 0.001). Conclusions – Screening for the clinical features of SS should be performed in patients with MS both receiving treatment with immunomodulatory drugs and without therapy.     

Chronic pain in urological diseases: a clinical review

Chronic pain is the central problem in a variety of urological diseases. Pain is an unpleasant sensory and emotional experience associated with either actual or potential tissue damage, or described in terms of such damage. The aim of this research was to update knowledge about the ultrastructural, clinical, psychological and therapeutic aspects of chronic pain in urological diseases, in particular in chronic pelvic syndrome. In this paper we have revisited the most significant and discussed articles published in the last twenty five years, with particular references on the 2008 European Guidelines, searching key words (chronic pelvic pain syndrome, chronic pelvic pain, chronic prostatitis, interstitial cystitis, prostatodynia, urological disease) and data with a high level of evidence. The articles that we have analyzed show that pain is characterized by an initial tissue injury that can lead to sensitization, which is a decrease in the intensity of the stimulus needed to elicit a response by the nerve, involving the peripheral and central nervous systems. The chronic pain state is characterized by loss of inhibitory interneurons, establishment of aberrant excitatory synaptic connections and long-term potentiation of response due to changes in sensitivity of nerve synapses. Stress and hormones might also play a role in central sensitization. Pain also has a cognitive and emotional component. It is very difficult to treat, given the complex nature of the response and the interaction of physiological aspects     

Gene expression profile analysis of AIDS-related primary effusion lymphoma (PEL) suggests a plasmablastic derivation and identifies PEL-specific transcripts

AIDS-related primary effusion lymphoma (PEL) is an HIV-associated malignancy characterized by the ability of the tumor cells to specifically home in the serous body cavities. Here we used gene expression profile analysis (about 12 000 genes) to further define the phenotype of PEL and to investigate the lymphoma relationship to normal B cells and to other tumor subtypes, including non-Hodgkin lymphomas (NHLs) of immunocompetent hosts and AIDS-associated NHL (AIDS-NHL). The results showed that PEL displayed a common gene expression profile that is clearly distinct from all NHLs of immunocompetent hosts and AIDS-NHL subtypes and, in contrast to those, is not related to germinal center (GC) or memory B cells. The gene expression profile of PEL was defined as plasmablastic because it showed features of both immunoblasts identified by Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines and AIDS immunoblastic lymphoma, and plasma cells, as defined by multiple myeloma cell lines. Finally, our results identify a set of genes specifically expressed in PEL tumor cells. Their expression was validated at the protein level, suggesting their potential pathogenetic and clinical significance.