Psoriasis comorbidity affects multiple sclerosis neurological progression: a retrospective case - control analysis.

BACKGROUND: Multiple sclerosis (MS) and psoriasis are inflammatory disorders, with epidemiological and biological associations. The impact of one disease on the course of the other has not been studied. OBJECTIVE: To characterize patients with psoriasis and MS, and to assess whether psoriasis comorbidity affected the progression of MS. METHODS: A retrospective case-control study. Patients with psoriasis comorbidity were identified from 3456 patients included in the Sheba Hospital Multiple Sclerosis Center database. Clinical and demographical characteristics and MS progression-related outcomes in patients whose follow-up exceeded 5 years were analysed and compared to those of a matched control cohort of MS-only (MSO) patients. RESULTS: Forty-five (1.3%) MS patients had psoriasis comorbidity. Psoriasis preceded MS in 35 (78%) cases. The psoriasis was defined as mild, moderate and severe in 24 (53%), twelve (27%) and nine (20%) cases respectively. MS progression-related outcomes were evaluated in 35 patients that had follow-up over 5 years. Patients with psoriasis onset preceding relapsing-remitting MS (RRMS) had slower progression of disease compared to MSO patients, as manifested by a longer time to second relapse (P < 0.01) and a longer time to significant neurological disability scores (P < 0.03). CONCLUSION: Psoriasis comorbidity preceding the onset of MS is associated with slower progression of disability.

Common and specific signatures of gene expression and protein-protein interactions in autoimmune diseases.

The aim of this study is to understand intracellular regulatory mechanisms in peripheral blood mononuclear cells (PBMCs), which are either common to many autoimmune diseases or specific to some of them. We incorporated large-scale data such as protein-protein interactions, gene expression and demographical information of hundreds of patients and healthy subjects, related to six autoimmune diseases with available large-scale gene expression measurements: multiple sclerosis (MS), systemic lupus erythematosus (SLE), juvenile rheumatoid arthritis (JRA), Crohn's disease (CD), ulcerative colitis (UC) and type 1 diabetes (T1D). These data were analyzed concurrently by statistical and systems biology approaches tailored for this purpose. We found that chemokines such as CXCL1-3, 5, 6 and the interleukin (IL) IL8 tend to be differentially expressed in PBMCs of patients with the analyzed autoimmune diseases. In addition, the anti-apoptotic gene BCL3, interferon-γ (IFNG), and the vitamin D receptor (VDR) gene physically interact with significantly many genes that tend to be differentially expressed in PBMCs of patients with the analyzed autoimmune diseases. In general, similar cellular processes tend to be differentially expressed in PBMC in the analyzed autoimmune diseases. Specifically, the cellular processes related to cell proliferation (for example, epidermal growth factor, platelet-derived growth factor, nuclear factor-κB, Wnt/ß-catenin signaling, stress-activated protein kinase c-Jun NH2-terminal kinase), inflammatory response (for example, interleukins IL2 and IL6, the cytokine granulocyte-macrophage colony-stimulating factor and the B-cell receptor), general signaling cascades (for example, mitogen-activated protein kinase, extracellular signal-regulated kinase, p38 and TRK) and apoptosis are activated in most of the analyzed autoimmune diseases. However, our results suggest that in each of the analyzed diseases, apoptosis and chemotaxis are activated via different subsignaling pathways. Analyses of the expression levels of dozens of genes and the protein-protein interactions among them demonstrated that CD and UC have relatively similar gene expression signatures, whereas the gene expression signatures of T1D and JRA relatively differ from the signatures of the other autoimmune diseases. These diseases are the only ones activated via the Fcɛ pathway. The relevant genes and pathways reported in this study are discussed at length, and may be helpful in the diagnoses and understanding of autoimmunity and/or specific autoimmune diseases.

Approach to determine nodal surfaces of some s-electron systems.

The paper is devoted to the study of the nodal surfaces of the wave functions for fermion systems. Using the quantum Monte Carlo method, implicit equations of nodal surfaces for some s-electron systems containing two-five electrons are numerically obtained. The obtained results are in agreement with the provisions of other researchers. An original method for constructing nodal surfaces is proposed, which is convenient for the implementation of quantum Monte Carlo.

Mucormycosis in a liver allograft: salvage re-transplantation and targeted immunosuppressive management.

Zygomycetes infection is associated with a high mortality in transplant populations. We describe a child with liver allograft Rhizopus oryzae infection who was salvaged by liver re-transplantation. A 10-year-old child presented with anastomotic bile leak that was repaired. A combined antibiotics and voriconazole regimen was introduced for Escherichia coli and Candida krusei growth in the peritoneal fluid. Despite broad antibiotic and antifungal coverage, the patient continued to have an ongoing infection. A follow-up computed tomography scan 8 weeks later showed 2 liver abscesses infiltrating the stomach and the diaphragm, with splenic infarcts and pericardial effusion. Aspirated samples from the liver abscess and the pericardial fluid revealed R. oryzae. Immunosuppression was discontinued and an antifungal regimen combining amphotericin B, posaconazole, and caspofungin was introduced. After 3 weeks of treatment with control of the systemic signs of infection, a positron emission tomography showed the fluorescence stain limited to the liver. With infection confined to the liver, the child underwent liver re-transplantation, splenectomy, and partial gastrectomy. Immunosuppression was reintroduced with recovery of the immune response observed by the CD4 cells adenosine triphophate release (Cylex(™) ImmuKnow(®) assay) and posaconazole was continued for another year. At 3-year follow-up, the child maintained normal graft function. We conclude that discontinuation of immunosuppression combined with a modern antifungal regimen may allow salvage re-transplantation in patients with liver mucormycosis.

[Holter monitoring for short-term prognostication in patients with myocardium infarction].

Individualized prognosis is a topical problem in the management of acute myocardial infarction. Prediction of clinical course and outcome of the disease encounters many difficulties since it requires highly sensitive and specific measurements that must be safe and technically simple. Prognostic studies related to acute myocardial infarction are many, but combined effect of various factors remains poorly known. Thus far, clinical conditions of the patients were evaluated largely based on medical history data and assays of cardiospecific enzymes. The expected outcome of the disease was deduced from the results of complicated and expensive studies (e.g. coronaroventriculography) available in relatively few medical centres or VEM test usually performed since the 3d week after onset of the disease. Most publications do not mention the use of 24 hour ECG (Holter) monitoring for immediate prognosis although this method is readily available, safe, and can be applied at any stage of the disease. Its sensitivity and specificity for the diagnosis of coronary heart disease is 88 and 69% respectively. The method can be used to evaluate efficiency of therapy, detect arrhythmogenic complications and painless myocardial ischemia in patients with myocardial infarction.

Avascular necrosis of the 1st metatarsal head.

Idiopathic avascular necrosis of first metatarsophalangeal head in child is unique condition not described in literature in past exlude one case. It seems to be part of avascular bone necrosis syndromes, like Freiberg disease, Sever disease etc. and the same principles of treatment are appropriate in AVN of 1st MTT head. We describe the case of bilateral AVN of 1st MTT head treated conservatively with complete cure.

Experimental Autoimmune Encephalomyelitis Ameliorated by Passive Transfer of Polymerase 1-Silenced MOG35-55 Lymphatic Node Cells: Verification of a Novel Therapeutic Approach in Multiple Sclerosis.

In the current study, we present an innovative concept based on the knowledge that enhancing naturally occurring biological mechanisms is effective in preventing neuronal damage and maintaining low disease activity in about 15% of multiple sclerosis (MS) patients presenting the benign type of MS. Recently, we have demonstrated that low disease activity in benign MS is associated with suppression of RNA polymerase 1 (POL1) pathway; therefore, targeting POL1 transcription machinery as a strategy for suppressing active forms of MS is suggested. To further establish our approach, we aimed to suppress POL1 pathway by silencing of the POL1-related RRN3, POLR1D and LRPPRC genes in specific MOG35-55-activated lymphocytes and assess their capacity to induce experimental autoimmune encephalomyelitis (EAE) by passive transfer. We have demonstrated that silencing of specific POL1 pathway-related genes significantly decreased viability and increased the proportion of CD4+/AnnexinV+/PI+ apoptotic cells in MOG35-55-primed lymphocytes. POL1-gene silencing significantly decreased the proportion of CD4+IL17+ and increased proportion of CD4+IL10+ and CD4+TNFa+ lymphocytes that occurred simultaneously with over-presentation of Treg CD4+CD25+FoxP3+ cells. Passive transfer of MOG35-55-primed lymphocytes after POL1-gene silencing suppressed EAE development in mice as demonstrated by delayed onset and peak of disease accompanied by significantly lower maximal and cumulative EAE scores. Our study supports a basis for direct targeting of POL1 transcription pathway as a strategy for selective induction of apoptosis and suppression of inflammation in EAE and consequently paves the way for innovative and targeted MS therapeutic strategy that is based on naturally existing biological mechanism.

RAM-589.555 a new Polymerase-1 inhibitor as innovative targeted-treatment for multiple sclerosis.

Targeting Polymerase-1 (POL1) transcription machinery is a new strategy for suppression of multiple sclerosis (MS) disease activity that is based on suppression of ribosomal biogenesis and subsequent activation of apoptosis. We developed an oral POL1 inhibiting compound RAM-589.555, that suppress ribosomal biogenesis as an innovative therapeutic approach to ameliorate MS. RAM-589.555 shows high permeability, specificity to POL1 pathway, ability to induce apoptosis and to inhibit proliferation and viability of activated lymphocytes both in-vitro and in-vivo. Moreover, oral administration of RAM-589.555 blocks ribosomal RNA transcription and significantly suppresses and ameliorates experimental autoimmune encephalomyelitis (EAE).

Peripheral blood gene expression signature mirrors central nervous system disease: the model of multiple sclerosis.

Global gene expression analysis using cDNA microarrays has proven to be a sensitive method to gain insight into molecular pathways mediating multiple sclerosis (MS) activity and to develop and refine the molecular taxonomy of the disease. This method was applied as a tool to investigate molecular heterogeneity of MS related gene transcripts in the aim of distinguishing between transcripts that trigger disease activity and account for direct genotype-phenotype correlation, and those whose expression is altered as a downstream effect of other genes. This review summarizes the current state of gene expression microarray applications for the study of MS, and specifically emphasizes the results of gene expression studies using peripheral blood mononuclear cells (PBMC) that were shown to be useful for better understanding of disease related pathways, monitoring of therapeutic responses to various drugs and prediction of clinical outcome. In the long run it is expected that the information provided by cDNA microarrays experiments will allow the determination of key molecular players involved in MS pathogenesis, and lead to better management of the disease using targeted treatments that will prevent its progression.

[Atrial fibrillation (the questions of etiology, classification, and treatment)].

The issue of atrial fibrillation is covered in the article in detail; the frequency of its individual forms is presented. The systematization of the individual forms of atrial fibrillation, the pathogenesis of its various forms, their reversibility and constancy are given from up-to-date positions. The author adduces a detailed description of modern methods of pharmacotherapy and instrumental therapy.

[Significance of C-reactive protein detection in patients with primary infective myocarditis].

The importance of the problem of primary infective endocarditis (PIE) has become much greater during the last years due to an increase in its incidence, serious early diagnostic difficulties, and high lethality, which makes study of its new diagnostic criteria necessary. The paper presents data on the role of C-reactive protein (CRP) in PIE diagnosis. The authors show that high CRP levels evidence prominent infective-and-toxic manifestations of the disease and that dynamic measurement of CRP levels in patients with infective myocarditis allows monitoring the effectiveness of the therapy and may be applied to the prognosis of the disease.

[Clinical efficacy and safety of terazosine (setegis) in patients with benign prostatic hyperplasia with concomitant cardiovascular diseases].

The aim of the study was assessment of clinical efficacy and safety of terazosine (setegis) in patients with benign prostatic hyperplasia (BPH) and concomitant cardiovascular disease. A total of 62 BPH patients with cardiovascular disease (ischemic heart disease, hypertension) having indications for alpha-adrenoblockers (mean age 74 +/- 11 years, 58-85) received terazosine in a dose 1-5 mg for 2 months. Clinical efficacy of terazosine was assessed by IPSS scale, residual urine, maximal voiding velocity. Safety of the drug was controlled by monitoring of arterial pressure, ECG, echo-CG. All the tests were made before therapy, on the treatment week 2, 4 and 8. The response was 90.3%. Overall symptoms score decreased by 37.0%, quality of life score rose by 23.8%. Amount of residual urine fell by 64.8%, maximal voiding velocity increased by 36.6%. Moderate effects of the drug (vertigo, weakness) occurred in 11.3% patients for 1 or 2 days after start of the therapy and were due to a moderate fall of arterial pressure in normotensive patients. Later artertial pressure stabilized, ECG registered no exacerbations of ischemic heart disease, no anginal attacks, no change in cardiac rhythm. Thus, terazosine (setegis) is effective and safe in BPH patients with cardiovascular disease. Pretreatment consultation of the cardiologist is desirable for correction of basic antianginal therapy.

Concern about falling is associated with step length in persons with multiple sclerosis.

BACKGROUND: Fear of falling is one of the major concerns of people with multiple sclerosis (MS). Although, it is likely that associations between spatio-temporal gait parameters and fear of falling exist in the MS population, these relationships have never been extensively studied. AIM: Aim of the study was to determine if fear of falling is associated with spatio-temporal gait parameters in persons with MS. DESIGN: Cross sectional study with a control group. SETTINGS: Multiple Sclerosis Center, Sheba Medical Center, Tel-Hashomer, Israel. METHODS: One-hundred and thirty relapsing-remitting patients diagnosed with MS, 79 women and 51 men aged 42.6 (SD=11.9), participated in this investigation. Twenty-five healthy subjects, 14 women and 11 men aged 38.5 (SD= 12.3), served as controls. Spatio-temporal parameters of gait were studied using the GAITRiteTM system (CIR Systems Inc., NJ, USA); Falls Efficacy Scale International (FES-I) was used to assess the level of concern relating to falls. Participants who scored >20 were classified as more concerned (N.=83), while those scoring ≤20 were defined as less concerned (N.=47). RESULTS: More concerned participants walked slower, took smaller steps, prolonged double support phase, wider base of support and a shorter single support phase compared to the less concerned group. According to step one of the multiple linear regression model, the spatial gait component accounted for 30.9% of the variance related to fear of falls (F=56.3, P<0.001). Step two added the gait temporal component, thus increasing the variance to 36.7% (F=36.2, P<0.001). Step three added the gait asymmetry parameters, thus increasing the predictor model to account for 40.3% of the variance in fear of falling (F=29.6, P<0.001). CONCLUSION: The present study provides quantitative evidence establishing spatio-temporal gait performance in individuals with MS relative to the level of fear of falling. CLINICAL REHABILITATION IMPACT: Spatio-temporal gait parameters may aid in assessing the level of fear of falling in people with MS. Step length may also serve as a surrogate outcome for assessing outcomes of interventions aimed at reducing fear of falling in the MS population.

The role of laquinimod in modulation of the immune response in relapsing-remitting multiple sclerosis: Lessons from gene expression signatures.

Laquinimod, is a potential oral immunomodulatory drug, for relapsing-remitting multiple sclerosis (RRMS). We analyzed the blood-transcriptional changes in RRMS patients (who participated in the ALLEGRO clinical trial) at one and six months after laquinimod treatment using gene expression microarrays. The molecular effects of laquinimod were enhanced by duration of treatment and showed down-regulation of inflammatory responses mainly via TGFb signaling, and of pro-inflammatory cytokines as well as of cellular movement, including adhesion, migration and leukocyte extravasation signaling. Our results demonstrate that laquinimod suppresses inflammation through down-regulation of inflammatory cytokines and arrest of leukocyte extravasation and thereby could attenuate disease activity in RRMS patients.

Expression of functional luteinizing hormone (LH) receptor and its messenger ribonucleic acid in bovine uterine veins: LH induction of cyclooxygenase and augmentation of prostaglandin production in bovine uterine veins.

We have previously reported that bovine endometrium contains LH/human CG binding receptors and LH induces cyclooxygenase and prostaglandin production in the bovine endometrium. The present study investigated 1) whether bovine uterine vein and artery contain LH receptor messenger RNA (mRNA) and receptor protein and 2) whether LH can regulate the formation of vasoactive eicosanoids by the uterine vein. The uterine vein endothelium, but not the uterine artery, contained LH receptor mRNA transcript essentially identical to that found in the bovine corpus luteum. The uterine vein endothelium also contained a 95-kDa immunoreactive receptor protein that bound to rat anti-LH receptor antibody in Western blots. The LH receptor mRNA and LH receptor were maximally expressed in the uterine vein from cows in proestrus/estrus compared with cows in luteal or postovulatory phases. Incubation of endothelial minces of uterine vein with LH resulted in a 2-fold increase in cyclooxygenase concentration as determined by Western blot using an antibody to ram seminal vesicle cyclooxygenase. The increase in cyclooxygenase was maximal in cows in proestrus/estrus compared with postovulatory and luteal phase cows. Incubation of proestrous/estrous uterine vein or artery minces with LH or mellitin (a phospholipase A2 stimulator) caused increased production of eicosanoids. In the uterine vein, LH caused a significant increase in both PGF2alpha (basal 4.1 +/- 0.4 vs. 5.7 +/- 0.4 ng/100 mg x 6 h, P < 0.01; N = 9 cows) and PGE2 (basal 5.7 +/- 0.3 vs. 7.7 +/- 0.8 ng/100 mg x 6 h, P < 0.01; N = 6 cows) but had no effect on prostaglandin production by the artery. Mellitin increased PGF2alpha production by both uterine vein and artery minces but had no effect on PGE2 production in either tissue. Addition of steroids (progesterone, estradiol) or cytokines (tumor necrosis factor-alpha, IL-6) to the uterine vascular tissues had essentially no effect on prostanoid production. In summary, bovine uterine vein from proestrous/estrous cows expressed the LH receptor and its mRNA. Expression of the receptor may have physiological significance as LH induces cyclooxygenase and increases prostaglandin release in the uterine vein. The maximal stimulation of the receptor and its mRNA at proestrus/ estrus may serve to increase the amounts of prostanoids reaching the regressing corpus luteum either directly by increasing prostanoid production or indirectly by increasing the blood flow to the ovary.

Intravenous immunoglobulin treatment following the first demyelinating event suggestive of multiple sclerosis: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Intravenous immunoglobulin (IVIg) has been reported to reduce disease activity in patients with relapsing-remitting multiple sclerosis. We assessed the effect of IVIg treatment in patients after the first neurological event suggestive of demyelinative disease and evaluated the occurrence of a second attack and dissemination in time demonstrated by brain magnetic resonance imaging within the first year from onset. METHODS: We conducted a randomized, placebo-controlled, double-blind study in 91 eligible patients enrolled within the first 6 weeks of neurological symptoms. Patients were randomly assigned to receive IVIg treatment (2-g/kg loading dose) or placebo, with boosters (0.4 g/kg) given once every 6 weeks for 1 year. Neurological and clinical assessments were done every 3 months, and brain magnetic resonance imaging was performed at baseline and the end of the study. RESULTS: The cumulative probability of developing clinically definite multiple sclerosis was significantly lower in the IVIg treatment group compared with the placebo group (rate ratio, 0.36 [95% confidence interval, 0.15-0.88]; P = .03). Patients in the IVIg treatment group had a significant reduction in the volume and number of T2-weighted lesions and in the volume of gadolinium-enhancing lesions as compared with the placebo group (P = .01, P = .01, and P = .03, respectively). Treatment was well tolerated, compliance was high, and incidence of adverse effects did not differ significantly between groups. CONCLUSIONS: Intravenous immunoglobulin treatment for the first year from onset of the first neurological event suggestive of demyelinative disease significantly lowers the incidence of a second attack and reduces disease activity as measured by brain magnetic resonance imaging.

Functional importance of bovine myometrial and vascular LH receptors and cervical FSH receptors.

Bovine myometrium and cervix contain luteinizing hormone/human chorionic gonadotropin (LH/hCG) binding sites, LH receptor (LH-R) messenger RNA (mRNA), and LH-R protein. Expression of LH-R is dependent on the stage of the cycle. LH-R expression is high during the luteal phase but weak during the follicular phase. In both myometrium and cervix, LH activates both the adenylate cyclase and phospholipase C pathways, and the effect of LH on both pathways at each stage of the cycle is correlated with the amount of LH-R present in the tissue. Because activation of cyclic AMP (cAMP) is associated with myometrial quiescence, we suggest that LH activation of uterine cAMP could serve to keep the uterus quiescent during the luteal phase. On the other hand, in the uterine vein LH-R mRNA and LH-R are maximal during preestrus/estrus as opposed to the luteal phase. In the uterine vein, LH increases the expression of cyclooxygenase and production of both prostaglandin E2 (PGE2) and PGF2 alpha. Because PGF2 alpha is the physiological luteolytic signal in the cow, we suggest that this increase in prostaglandin production by the uterine vein is part of the physiological events leading to luteolysis. In addition to uterine LH-R, the bovine cervix at preestrus/estrus has high levels of follicle-stimulating hormone receptor (FSH-R) and its corresponding mRNA. As with LH-R, activation of FSH-R by FSH is associated with activation of a G protein-coupled receptor family that mediates the cAMP and inositol phosphate signaling pathways. Activation of these signaling pathways is associated with an increase in the expression of cyclooxygenase and production of PGE2. Because expression of the FSH receptor was maximal at the time of the FSH peak in the blood, we suggest a physiological role for FSH in the cervix relaxation and opening at estrus.

Hassles, health, and personality.

College undergraduates (N = 211) responded to a "decontaminated" hassles scale plus measures of trait anxiety, reactivity, perceived stress, psychiatric symptomatology, and minor physical ailments. All but the anxiety and reactivity scales were time referenced to the past month. Major findings were as follows: (a) Hassles and trait anxiety both contributed positively to perceived stress, jointly accounting for 58% of the variance; (b) hassles and reactivity both had a significant positive impact on minor ailments, together explaining 23% of the variance; and (c) hassles and trait anxiety had a significant interactive effect on psychiatric symptomatology, which along with the nonsignificant marginal main effects accounted for 67% of the variance. The positive impact of hassles on psychiatric symptomatology increased as trait anxiety rose; likewise, the pathogenic effect of trait anxiety increased with greater exposure to hassles.

Induction of cyclooxygenase and prostaglandin E2 production by the bovine pre-embryo.

A study was conducted to determine the induction of cyclooxygenase production in the cleaved and non-cleaved oocyte and to measure the secretion of prostaglandin E2 (PGE2), PGF2 alpha and tumour necrosis factor-alpha (TNF alpha) in the conditioned medium of non-mature oocytes (denuded), mature oocytes (oocyte-cumulus complex), cleaved oocytes, and non-cleaved oocytes (mature oocytes incubated in the absence of sperm). Cyclooxygenase was readily detectable in 48-h cleaved oocytes whereas the signal for the enzyme in the non-cleaved oocytes was weak or undetectable. Cyclooxygenase expression in the cleaved oocytes was transient and enzyme concentrations at the early morula stage (72 h) were low. Measurable amounts of both PGE2 and TNF alpha were secreted during the first 24 h of maturation and 6 h after fertilization, whereas PGF2 alpha was undetectable at these times. There was a dramatic enhancement in PGE2, PGF2 alpha and TNF alpha secretion 48 h after fertilization. At 72 h after fertilization, PGE2 concentrations were much lower and PGF2 alpha was again undetectable which corresponded to a low concentration of cyclooxygenase. In contrast, high TNF alpha activity continued to be detected even 72 h after fertilization. It is possible that the induction of the production of cyclooxygenase and the secretion of PGs and TNF alpha by fertilized oocytes at specific times after fertilization plays a role in the regulation of embryonic development, maternal immunological recognition of pregnancy, and the maintenance of a suitable hormonal environment for embryonic viability.

Prostaglandin production by the oocyte cumulus complex around the time of fertilization and the effect of prostaglandin E on the development of the early bovine embryo.

The oocyte-cumulus complex (25 oocytes per 250 microL medium) produced prostaglandin-F2 alpha (PGF2 alpha) and PGE2 during maturation, immediately following fertilization and for at least 48 h after fertilization. The data suggest that PG production is important in the development of the oocyte; addition of PGE2 (5 ng mL-1) to the fertilization medium increased the rate of cleavage and groups of oocytes with low cleavage rates produced far less PG than groups with high cleavage rates. Measurement of PG in the maturation medium could therefore be a means of assessing the suitability of oocytes for fertilization.