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M Mandel

Publications and source records attributed to M Mandel.

At least 19 recordsLinked to original sources
PubMed2006

Gene expression studies in systemic lupus erythematosus.

In a single assay, gene microarrays generate tens of thousands of measurements for the relative levels of messenger RNA expression, and thus hold promise to uncover the regulation of transcriptional responses behind clinical phenotypes of various diseases. Systemic lupus erythematosus (SLE) offers a unique opportunity to study gene expression both systemically and organ specific, as the tissues involved and specifically peripheral blood cells are readily accessible for molecular analysis. In the current review we highlight the current knowledge related to gene microarray in SLE. We approached the following questions: 1) Can gene microarray technology be used to translate molecular profiles into meaningful and applicable clinical information? 2) Does the assessment of differential gene expression provide specific signatures that may contribute to diagnostic and prognostic markers of SLE? 3) Can clinicians be helped in monitoring disease activity by identification of drug response gene profile? 4) Does evaluation of differential gene expression provide clues to detect previously unrecognized genes associated with the disease? It is evident that though not all questions can be currently answered appropriately, gene expression studies in SLE have important implications and will not only be beneficial for SLE patients, but will also lead to a better understanding of other autoimmune inflammatory diseases, thereby leading to novel diagnostic and therapeutic strategies in autoimmunity.

Autoimmunity↗
PubMed2005

Evaluating survival model performance: a graphical approach.

In the last decade, many statistics have been suggested to evaluate the performance of survival models. These statistics evaluate the overall performance of a model ignoring possible variability in performance over time. Using an extension of measures used in binary regression, we propose a graphical method to depict the performance of a survival model over time. The method provides estimates of performance at specific time points and can be used as an informal test for detecting time varying effects of covariates in the Cox model framework. The method is illustrated on real and simulated data using Cox proportional hazard model and rank statistics.

Humans↗
PubMed2005

Increased risk of bloodstream and urinary infections in intensive care unit (ICU) patients compared with patients fitting ICU admission criteria treated in regular wards.

Critically ill patients, eligible for admission into intensive care units (ICUs), are often hospitalized in other wards due to a lack of ICU beds. Differences in morbidity between patients managed in ICUs and elsewhere are unknown, specifically the morbidity related to hospital-acquired infection. Patients fitting ICU admission criteria were identified by screening five entire hospitals on four separate days. Hospital infections within a 30-day follow-up period were compared in ICU patients and in patients on other wards using Kaplan-Meier curves. Residual differences in the patients' case mix between ICUs and other wards were adjusted for utilizing multivariate Cox models. Of 13415 patients screened, 668 were critically ill. The overall infection rates (per 100 patient-days) were 1.2 for bloodstream infection (BSI) and 1.9 for urinary tract infection (UTI). The adjusted hazard ratios in ICU patients compared with patients on regular wards were 3.1 (P<0.001) for BSI and 2.5 (P<0.001) for UTI. This increased risk persisted even after adjusting for the disparity in the number of cultures sent from ICUs compared with ordinary wards. No interdepartmental differences were found in the rates of pneumonia, surgical wound infections and other infections. Minimizing the differences between characteristics of patients hospitalized in ICUs and in other wards, and controlling for the higher frequency of cultures sent from ICUs did not eliminate the increased risk of BSI and UTI associated with admission into ICUs.

Aged↗
PubMed2004

T cell vaccination in multiple sclerosis relapsing-remitting nonresponders patients.

Myelin autoreactive T cells are involved in the pathogenesis of multiple sclerosis (MS) and lead to propagation of the disease. We evaluated the efficacy of T cell vaccination (TCV) therapy for patients with aggressive relapsing-remitting MS who failed to respond to immunomodulatory treatments. Twenty nonresponders relapsing-remitting MS patients were immunized with autologous attenuated T cell lines after activation with synthetic myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) encephalitogenic peptides. Each patient received three vaccinations in 6- to 8-week intervals. Annual relapse rate decreased from 2.6 to 1.1, P = 0.026. Neurological disability stabilized as compared with the 2- and 1-year pretreatment progression rates. Significant reduction in the number and volume of active lesions, as well as reduction in T2 lesion burden, was demonstrated by quantitative MRI analysis. No serious adverse events were observed. Our findings suggest that TCV has beneficial clinical effects in MS patients who, in spite of immunomodulatory treatments, continue to deteriorate. TCV could serve as a potential alternative therapy for this subgroup of nonresponders patients.

Adult↗
PubMed2004

Autoimmunity gene expression portrait: specific signature that intersects or differentiates between multiple sclerosis and systemic lupus erythematosus.

Autoimmune diseases are either tissue-specific like multiple sclerosis (MS) or multisystemic like systemic lupus erythematosus (SLE), although clinically both exhibit common features. To gain insight into the properties of the genes involved in each disease we have investigated the gene expression signature of peripheral blood mononuclear cells (PBMC) in MS and SLE in comparison to healthy subjects. Total RNA was purified, hybridized to Genechip array and analysed in 36 subjects (13 relapsing-remitting MS patients, five SLE patients and 18 age-matched healthy subjects that served as controls). Additional blood samples from 15 relapsing-remitting MS patients, 8 SLE patients and 10 healthy subjects were used for confirmation of microarray gene expression findings by ELISA and RT-PCR. MS and SLE patients demonstrated a common gene expression autoimmune signature of 541 genes which differentiated them from healthy subjects. The autoimmune signature included genes that encode proteins involved in apoptosis, cell cycle, inflammation and regulation of matrix metalloproteinase pathways. Specifically, decreased TIMP1 gene expression in the autoimmunity signature suggests increased MMP activity in target tissues as a result of the lack of feedback mechanism. An additional different disease specific signature identified the gene expression pattern for MS (1031 genes), mainly associated with over-expression of adhesion molecules and down-expression of heat shock proteins; the SLE specific signature (1146 genes) mainly involved DNA damage/repair pathways that result in production of nuclear autoantibodies. These results provide insights into the genetic pathways underlying autoimmune diseases, and identify specific disease-associated signatures that may enable targetted disease-related specific therapies to be developed.

Adult↗
PubMed2001

Comparison of the prevalence of glutamic acid decarboxylase (GAD65) and gliadin antibodies (AGA) in a randomly selected adult estonian population.

We aimed to test the hypothesis that gluten might be associated with the development of islet cell autoimmunity. A random sample of 200 persons (87 males, mean age 42.4 years) from Estonia including one patient with type I diabetes mellitus was studied. IgG-type glutamic acid decarboxylase (GAD65) antibodies were determined using radioligand-binding assay and IgG/IgA-type gliadin antibodies (AGA) by enzyme-linked immunosorbent assay. Generic HLA-DRB1* alleles were analyzed using a polymerase chain reaction. Although our results revealed the highest GAD65Ab index and a high IgA-type AGA in a person with diabetes, no correlation between GAD65Ab and AGA values was revealed among the other 199 persons (p > 0.05). There were also no differences between test values among persons with and without different HLA-DRB1* alleles (p > 0.05). In the GAD65Ab assay, one person (0.5 %; 95 % CI: 0 - 1.5) out of 199 exceeded the 99(th) centile of the GAD65Ab index. In summary, the present study does not confirm the possibility that there is a relationship between the immune reactivity against GAD65 and gliadin, at least in persons without type I DM.

Adolescent↗
PubMed2001

Anti-cancer activities of hypericin in the dark.

The potent photodynamic properties of hypericin (HY) elicit a range of light-dependent virucidal and tumoricidal activities. Yet, a relatively low reduction/oxidation potential endows HY with electron accepting and donating properties enabling it to act as both an oxidizing and a reducing agent. HY can thus compete as an electron acceptor from bioenergized reduction/oxidation reactions generating its excitation energy for biological activities from physiological reduction/oxidation reactions in the absence of light. Our studies show that HY can inhibit the growth of highly metastatic murine breast adenocarcinoma and squamous cell carcinoma tumors in culture. Furthermore, we show that HY can interfere with the growth of these tumors in mice reducing tumor size and prolonging animal survival in complete absence of light. While there is no evidence that HY induces apoptosis in these cells in the dark, 3H-thymidine incorporation into DNA was significantly reduced indicating effects that are apparently cytostatic in nature compared to the cytocidal effects of HY with light.

Animals↗
PubMed2000

Amplification of immunological functions by subcutaneous injection of intermediate-high dose interleukin-2 for 2 years after autologous stem cell transplantation in children with stage IV neuroblastoma.

BACKGROUND: Immunotherapy given post-autologous stem cell transplantation may eliminate residual tumor cells escaping the conditioning protocol. METHODS: Five children suffering from stage IV neuroblastoma were treated by recombinant interleukin-2 (IL-2) post-autologous peripheral blood stem cell transplantation. The patients' peripheral mononuclear cells were monitored for CD3+ and CD56+ levels, their proliferative response and killing of various cell lines targets. RESULTS: An increase in the level of total lymphocytes, mainly due to expansion of T cells, and enhanced proliferative response to phytohemaglutinin were observed. Elevated cytotoxicity against K562 and neuroblastoma target cells was detected in four patients and against K562 targets in one patient. Toxicity included mild thrombocytopenia, and fever in four patients and mild to moderate encephalopathy which necessitated withdrawing one patient from the protocol. Three of five patients studied are alive today, one of them whose IL-2 was stopped, is in relapse. Two patients have died. CONCLUSIONS: Immunotherapy with s.c. intermediate-high dose IL-2 is feasible and results in expansion of T cells and in stimulation of killing activity against several targets including in some cases, neuroblastoma tumor cells.

Child, Preschool↗
PubMed2000

The dielectric increments of aqueous polyelectrolyte solutions: a scaling approach

This paper deals with dielectric dispersion curves (covering a frequency range from a few Hz to 100 MHz) of Na-poly(styrene-sulfonate) of 65,000 < or = Mw < or = 1,060,000 g mol(-1) in aqueous solutions. The values of the low frequency (dielectric increment1) and high frequency (dielectric increment2) dielectric increments, obtained from the experimental curves matched to a superposition of two Cole-Cole equations, have been analyzed in terms of their concentration and molar mass dependence. The concentrations C (g l(-1)) of the various solutions were mostly situated in the transition regime defined by Odijk [T. Odijk, Macromolecules 12 (1979) 688] between the dilute regime (C < Cg*) and the semi-dilute one (C > C**), and wherein the characteristic concentration C* marks the onset of flexibility effects on the polyion behavior. It has been shown that in the concentration range Cg* < C < C** the increments in both frequency domains satisfy a scaling relation dielectric increment(j) = Bj M(nu j) (C/C*)(mu j) with molar mass independent exponents nu j and mu j changing around C*. Their values are different for dielectric increment1 and dielectric increment2, except for mu above C* where both increments appear to become concentration-independent. Below Cg*, in the dilute regime, the two dispersion domains seem to merge. The increment dielectric increment = relative permittivity (0) - high frequency limit of relative permittivity is molar mass independent if scaled to (C/Cg*). The molar mass dependence of the increments as a function of the macromolecular concentration rhoP, dielectric increment or dielectric increment(j) approximately Mgamma (rhoP)mu, also reveals differences between the different concentration regimes. Extrapolation from above Cg* to zero concentration is thus unjustified.

Journal Article↗
PubMed2000

The risk for cancer among children of women who underwent in vitro fertilization.

BACKGROUND: The possible association between ovarian carcinoma and ovulation-inducing drugs has led to renewed interest in the potential carcinogenic risks of these drugs. In vitro fertilization (IVF) has been linked to multiple pregnancies and possibly congenital malformations. However, to the authors' knowledge the association between IVF and pediatric cancer has been described only in sporadic case reports. The aim of this study was to assess the incidence rate of pediatric cancer among a cohort of children born after IVF. METHODS: A historic prospective study based on a cohort of 332 children from 1254 women who underwent IVF treatment between 1981-1994 was performed. Medical files were reviewed and names were linked to the National Population and Cancer Registries. Pediatric cancer incidence rates were compared with the expected age-adjusted rates of the general population during the respective time period. RESULTS: No cancer cases were observed among the study cohort with respect to 1.7 cases that were expected. CONCLUSIONS: Because the small cohort analysis in the current study lacked the necessary power to reach definite conclusions, larger prospective studies are needed to assess the potential carcinogenic effect on children born after ovulation induction and IVF.

Adult↗
PubMed2000

Fighting among Jerusalem adolescents: personal and school-related factors.

PURPOSE: To study the prevalence of physical fighting among youth and its association with personal and school-related factors. METHODS: Pupils in the 8th and 10th grades (n = 1182, ages 13-16 years) in 11 Jerusalem secular and religious schools anonymously completed the World Health Organization questionnaire from the Health Behavior in School Children study. The unit of analysis was defined as the number of times the student was involved in physical fighting during the past year. The independent variables studied were sociodemographic characteristics, personal, and school-related factors including teachers, peers, and family. RESULTS: Fighting at least once was reported by 76% of boys and 26% of girls; 6% of boys who were involved in fights at least once and 16% more than once required medical treatment. For boys, bullying others, poor health and mental health score, and perception of teachers that the pupil was a below-average student significantly increased the odds ratio (OR) for fighting more than once in the past year. Among girls, poor mental health, poor parental support on school matters, bullying, and being bullied by others increased the OR for fighting. CONCLUSIONS: Fighting is a highly prevalent behavior among adolescents irrespective of their socioeconomic background. Determinants differ by gender, and intervention programs should focus on the gender-specific determinants.

Adolescent↗
PubMed2000

Successful treatment of invasive aspergillosis in chronic granulomatous disease by granulocyte transfusions followed by peripheral blood stem cell transplantation.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder characterized by impaired microbial killing and susceptibility to bacterial and fungal infections. Cure of the disease can be achieved by stem cell transplantation when performed early in its course, and before severe infections have developed. Invasive aspergillosis constitutes a very high risk for transplantation. We report a 4-year-old boy with X-linked CGD who underwent successful HLA-identical peripheral blood stem cell (PBSC) transplantation during invasive pulmonary aspergillosis and osteomyelitis of the left fourth rib, which was unresponsive to antifungal treatment. During the 2 months prior to the transplant he received G-CSF-mobilized granulocyte transfusions (GTX) from unrelated donors three times a week in addition to the antifungal treatment. This resulted in clinical improvement in his respiratory status. He also received GTX during the aplastic period after the conditioning regimen, until he had engrafted. Post-transplant superoxide generation test revealed that neutrophil function was within normal range. One year post transplant the CT scan showed almost complete clearance of the pulmonary infiltrates and a marked improvement in the osteomyelitic process. Based on other reports and our own experience, GTX can serve as important treatment in patients with CGD who have failed conventional anti-fungal treatment and for whom stem cell transplantation is the only chance for cure.

Amphotericin B↗
PubMed2000

Inhibition of the CD8+ T cell-mediated cytotoxicity reaction by hypericin: potential for treatment of T cell-mediated diseases.

The cytotoxicity reaction of murine CD8 T lymphocytes has been found to be strongly inhibited by nanomolar concentrations of hypericin, a lipophilic dianthraquinone with photodynamic properties. Cytotoxic T lymphocyte (CTL)-induced target cell apoptosis, as well as exocytosis of cytolytic granules from these cells, were ablated by hypericin, administered at the onset of the reaction, without affecting CTL viability. The inhibition of cytolysis occurred without the light irradiation which is essential for photosensitization. The findings suggest that the action of hypericin targets the effector CTL; however, apoptosis induced in murine L-cells with recombinant tumor necrosis factor (TNF)-alpha was also prevented by hypericin. Since hypericin is a known inhibitor of protein kinase C, MAP kinase and at least one other tyrosine kinase, this inhibitory activity could play a role in the down-modulation of CTL-induced cytotoxicity. Furthermore, our studies show that the action of hypericin induces rapid dephosphorylation of phospholipids associated with low-density membranes in CTL, but not with membranes of the cytotoxic granules. The ability of hypericin to interfere with cytotoxicity may render it useful in the treatment of T cell-mediated diseases.

Animals↗
PubMed2000

Manometric changes during retrograde biliary infusion in mice.

The manometric, ultrastructural, radiographic, and physiological consequences of retrograde biliary infusion were determined in normostatic and cholestatic mice. Intraluminal biliary pressure changed as a function of infusion volume, rate, and viscosity. Higher rates of constant infusion resulted in higher peak intraluminal biliary pressures. The pattern of pressure changes observed was consistent with biliary ductular and/or canalicular filling followed by leakage at a threshold pressure. Retrograde infusion with significant elevations in pressure led to paracellular leakage of lanthanum chloride, radiopaque dye, and [(14)C]sucrose with rapid systemic redistribution via sinusoidal and subsequent hepatic venous drainage. Chronic extrahepatic bile duct obstruction resulted in significantly smaller peak intrabiliary pressures and lower levels of paracellular leakage. These findings indicate that under both normostatic and cholestatic conditions elevated intrabiliary volumes/pressures result in an acute pressure-dependent physical opening of tight junctions, permitting the movement of infusate from the intrabiliary space into the subepithelial tissue compartment. Control of intraluminal pressure may potentially permit the selective delivery of macromolecules >18-20 A in diameter to specific histological compartments.

Animals↗
PubMed2000

Strategies for evaluation of enveloped virus inactivation in red cell concentrates using hypericin.

Photodynamically induced virus inactivation appears promising in preventing transmission of enveloped virus infections in transfusible blood products. The potential for utilizing hypericin as a photosensitizer to inactivate key enveloped viruses in packed red cell concentrates (PRC) was evaluated. In addition to inactivating effectively > or = 10(6) TCID50 of human immunodeficiency virus (HIV), inactivation of bovine viral diarrhea virus (BVDV) in PRC was used as a model for hepatitis C virus to overcome the deficiency in reliable experimental systems for hepatitis C virus (HCV) inactivation. BVDV was two orders of magnitude more sensitive to inactivation by hypericin than HIV. As part of the virucidal efficacy analyses, the effects of photosensitization on hemopoietic cell lines carrying quiescent integrated HIV provirus were studied as models for evaluating virus inactivation in latently infected cells. Phorbol ester-induced virus production by these cells was effectively prevented by photosensitization with hypericin. A refinement of the illumination conditions, incorporating a monochromatic sodium light source with an emission spectrum coinciding with the absorption peak of hypericin, was highly virucidal, however, caused unacceptable levels of hemolysis. Red blood cells could be protected from phototoxic cellular damage by complexing hypericin with human serum albumin (albumin-hypericin), but the decrease in hemolysis was at the expense of virucidal efficacy. Thus, excitation of hypericin with a fluorescent source appears to be useful potentially for virus inactivation in PRC.

Animals↗