Vaccination with myelin oligodendrocyte glycoprotein adsorbed to alum effectively protects DBA/1 mice from experimental autoimmune encephalomyelitis

To prevent an organism from developing autoimmunity the body limits the number of autoreactive cells through thymic negative selection and regulates their activity through induction of suppressor T cells. Development of antigen-specific therapies provides an interesting opportunity to imitate the body's own, often effective, method of protection. Our study demonstrates that DBA/1 mice could be protected from experimental autoimmune encephalomyelitis induced through injection of recombinant myelin oligodendrocyte glycoprotein (rMOG) when they were previously immunized intraperitoneally with rMOG adsorbed to aluminium hydroxide. This protection was associated with a decreased IFN-gamma production by rMOG-specific cells, but not a decreased proliferative response. Protection was long lasting, indicating that MOG-alum vaccination might be developed as a prophylactic therapy in multiple sclerosis.     

Leigh Syndrome with COX deficiency and SURF1 gene mutations: MR imaging findings

Mutations in the nuclear SURF1 gene are specifically associated with cytochrome c oxidase (COX)-deficient Leigh syndrome. MR imaging abnormalities in three children with this condition involved the subthalamic nuclei, medulla, inferior cerebellar peduncles, and substantia nigra in all cases. The dentate nuclei and central tegmental tracts were involved in two cases each (all instances), and the putamina, interpeduncular nucleus, and pallido-cortical-nigro-cortical tracts in one. MR imaging pattern recognition can suggest an underlying COX deficiency and should prompt investigators to search for SURF1 gene mutations.     

The influence of cyclin D1 (CCND1) 870A>G polymorphism and CCND1-thymidylate synthase (TS) gene-gene interaction on the outcome of childhood acute lymphoblastic leukaemia

The 870A>G polymorphism in the cyclin D1 (CCND1) gene modulates mRNA splicing, leading to altered protein that may affect the regulation of the G1/S cell-cycle checkpoint. This polymorphism has been reported to influence susceptibility to and progression of several malignancies. Furthermore, the change of retinoblastoma protein regulation mediated by CCND1 may play a role in the development of methotrexate (MTX) resistance via an associated higher activity of enzymes that are inhibited by MTX. This study shows that children with acute lymphoblastic leukaemia (ALL) who are homozygous for the CCND1 A variant have a lower probability of event-free survival (P = 0.006) compared to carriers of the G variant. A significant result is retained in the presence of other prognostic factors. This impact is even more apparent in individuals who are also homozygous for thymidylate synthase (TS) triple repeat (P < 0.00005), which has previously been shown to influence the outcome of childhood ALL.     

Decreased repair activities of 1,N(6)-ethenoadenine and 3,N(4)-ethenocytosine in lung adenocarcinoma patients

To assess the role of oxidative stress and lipid peroxidation (LPO) in the pathogenesis of lung cancer, we measured the levels of 1,N(6)-ethenoadenine (epsilonA) and 3,N(4)-ethenocytosine (epsilonC) in the DNA by immunoaffinity/(32)P postlabeling (33 cases). We also measured the capacity for epsilonA and epsilonC repair (by the nicking assay) in normal and tumor lung tissues, as well as in blood leukocytes of lung cancer patients (56 cases). Repair activities for epsilonA and epsilonC were also assayed in leukocytes of healthy volunteers, matched with cancer patients for age, sex, and smoking habit (25 individuals). Up to 10-fold variations among individuals were observed both in adducts level and repair activities. No differences in epsilonA and epsilonC levels between tumor and nonaffected lung tissues were recorded. However, leukocytes accumulated a significantly higher number of DNA adducts than the lung tissues. Repair activities for both epsilonA and epsilonC were significantly higher in tumor than in normal lung tissue. No significant differences in epsilonA and epsilonC repair activities were associated with age, sex, or smoking habit. However, a significant difference in repair capacity was observed between two histological types of lung cancer, squamous cell carcinoma (SQ) and adenocarcinoma (AD). In individuals suffering from lung AD, epsilonA- and epsilonC-repair activities in normal lung and blood leukocytes were significantly lower than in SQ patients. Moreover, in nonaffected lung tissue of AD patients, the ratio epsilonA/epsilonC adducts was lower than in SQ patients. Differences have also been found between epsilonA and epsilonC repair activities of cancer patients and healthy volunteers. Repair capacity for epsilonA was significantly lower in blood leukocytes of lung cancer patients than in leukocytes of healthy volunteers (P = 0.012). This difference was even larger between healthy volunteers and patients developing inflammation-related AD (P = 0.00033). Repair activities for epsilonC were the same in leukocytes of healthy controls, all lung cancer patients, and SQ patients. However, individuals with ADs revealed significantly lower epsilonC-repair activity (P = 0.013). These results suggest that oxidative stress-mediated lipid peroxidation might contribute to induction and/or progression of lung cancer. Decreased activity of base excision repair pathway for epsilonA and epsilonC is associated particularly with inflammation-related lung AD.     

Prolonged signal-averaged P wave duration as a prognostic marker for morbidity and mortality in patients with congestive heart failure

OBJECTIVE: To evaluate the prognostic roles of prolonged signal-averaged P wave duration (SAPWD), raised levels of natriuretic peptides, and clinical characteristics in patients with stable congestive heart failure (CHF). DESIGN: The SAPWD was assessed from a signal-averaged electrocardiogram (SAECG), and the plasma levels of N-terminal pro-atrial natriuretic peptide (Nt-proANP) and N-terminal pro-brain natriuretic peptide (Nt-proBNP) were measured in 43 consecutive patients with stable CHF without prior supraventricular arrhythmia. Echocardiographic and clinical data were also recorded. Time to death, hospitalization due to deteriorated CHF, or ECG-documented atrial fibrillation (AF) was recorded over a 438-day median follow-up. RESULTS: During follow-up, 17 patients met an endpoint defined as death, AF, or hospitalization due to deteriorated CHF. Proportional hazard regression including the variables high age, prolonged SAPWD, raised levels of Nt-proANP and Nt-proBNP, and low ejection fraction (EF) showed that only prolonged SAPWD > or =149 ms was associated with an increased risk of meeting an early endpoint; the hazard ratio 3.94 with 95% confidence interval 1.50-10.42; p = 0.006. CONCLUSION: Prolonged SAPWD appears to predict early death, AF development, or hospitalization due to deterioration of CHF in patients with stable CHF.     

Long-term sertraline treatment and peripheral biochemical markers in female depressed patients

Serotonergic system is implicated in the pathogenesis of depression. Peripheral biochemical markers, platelet serotonin (5-HT) and platelet monoamine oxidase (MAO) activity were determined spectrofluorimetrically at baseline and after 4 and 24 weeks of sertraline (a selective serotonin reuptake inhibitor (SSRI)) treatment in 15 female nonsuicidal, nonpsychotic patients with major depression and compared with 15 drug-free healthy women. The aim of the study was to determine the effects of 4 and 24 weeks of sertraline treatment on platelet 5-HT concentration and platelet MAO activity in depressed patients subdivided according to the treatment response into remitters, responders and nonresponders after 4 and 24 weeks of sertraline treatment based on the 70%, 50-69% and <49% reductions in baseline Montgomery-Asperg Depression Rating Scale (MADRS) scores, respectively. Platelet 5-HT concentration was significantly lower in all depressed patients at baseline than in healthy subjects. Among patients, platelet 5-HT concentration or platelet MAO activity did not differ before treatment. There was no significant correlation between MADRS scores and peripheral biochemical markers. The limitation of the study was in a small number of patients, but its advantage was in a long-term (24 weeks) follow-up of both patients and healthy controls. Our results show that long-term sertraline treatment induced remission and response in 87% patients, decreased platelet 5-HT concentration after 4 and 24 weeks of treatment and decreased platelet MAO activity after 24 weeks and suggest that pretreatment values of platelet 5-HT and platelet MAO might not predict therapeutic outcome to sertraline treatment in female depressed patients.     

HLA genotypes and disease severity assessed by magnetic resonance imaging findings in patients with multiple sclerosis

The objective of the study was to examine the relationship between HLA genotypes and disease severity as measured by brain MRI quantitative markers of demyelinating and destructive pathology in patients with multiple sclerosis (MS). We studied 100 patients with MS and 122 age, sex-, ethnic- and residence-matched controls. The DNA extraction and the genomic typing (A, B, DRB1 and DQB1 loci) were obtained with sequence-specific oligonucleotide method, using a commercially available reversible line blot assay (INNO-LIPA). All patients underwent a 1.5 tesla MRI examination of the brain. Disease severity was assessed by clinical (Expanded Disability Status Scale (EDSS)) and MRI (T2- and T1-lesion load (LL) and brain parenchymal fraction (BPF)) outcome measures. HLA-DQB1* 02 (OR 19.9, 95% C. I. 16.2–24.3, uncorrected (uncorr)- p<0.00001, corr-p<0.0006), -DQB1*03 (OR 16.8, 95% C. I. 13.6–20.5, uncorr-p<0.00001, corrp< 0.0006), -DRB1*15 (OR 4.6, 95% C. I. 3.7–5.6, uncorrp= 0.0001, corr-p=0.006), and -DRB1*03 (OR 3.9, 95% C. I. 3.2–4.8, uncorr-p=0.0001, corrp= 0.006) alleles were associated with MS. T2-, T1-LL, BPF and EDSS were not significantly different according to the carrier status of these HLA alleles. No differences were found in the ratios of disease severity/disease duration according to the HLA car rier status. Multiple regression analysis showed that a higher T2-LL was associated with the presence of DRB1*04 (uncorr- R2=0.15, p=0.006 and corr- R2=0.11, p=0.025) and B7 alleles (uncorr-R2=0.08, p=0.02 and corr-R2=0.07, p=0.018), T1-LL was associated with B7 (uncorr- R2=0.30, p<0.0001 and corr- R2=0.27, p=0.0001) and DRB1*12 (uncorr-R2=0.25, p<0.0001 and corr-R2=0.21, p=0.0002) alleles, whereas the BPF was predicted only by the presence of DRB1*12 allele (uncorr-R2=0.24, p=0.002 and corr-R2=0.20, p=0.004). The study findings suggest that some HLA alleles may predict the destructive pathological processes visible on MRI. Since the size of the sample studied is relatively small, further studies are needed to draw any firm conclusion about genotype/phenotype correlation in patients with MS.