Interaction between clonal plasma cells and the immune system in plasma cell dyscrasias

The term "monoclonal gammopathy" (MG) includes a group of clonal plasma cell disorders, which show heterogeneous clinical behavior. While multiple myeloma (MM) and plasma cell leukemia (PCL) are incurable malignant diseases, most patients with MG of undetermined significance (MGUS) show an indolent/benign clinical course. Evidence has accumulated which supports the role of the bone marrow microenvironment in MG. Accordingly, the survival, drug-resistance and proliferation of MM cells have been shown to be largely dependent on a supportive microenvironment. Among the different environment-associated parameters, those related to the status/activity of the immune system are particularly relevant. This review focuses on the different ways clonal plasma cells (PC) interact with the immune system in different models of MG, to characterize crucial events in the development and progression of MG. These advances may support the design of novel therapeutic approaches in patients with MG.     

Nuclear monothiol glutaredoxins of Saccharomyces cerevisiae can function as mitochondrial glutaredoxins

Glutaredoxins are thiol oxidoreductases that regulate protein redox state. In Saccharomyces cerevisiae, Grx1 and Grx2 are cytosolic dithiol glutaredoxins, whereas Grx3, Grx4, and Grx5 are monothiol glutaredoxins. Grx5 locates at the mitochondrial matrix and is needed for iron/sulfur cluster biogenesis. Its absence causes phenotypes such as inactivation of iron/sulfur enzymes and sensitivity to oxidative stress. Whereas Grx5 contains a single glutaredoxin domain, in Grx3 and Grx4 a thioredoxin-like domain is fused to the glutaredoxin domain. Here we have shown that Grx3 locates at the nucleus and that the thioredoxin-like domain is required for such location. We have addressed the functional divergence among glutaredoxins by targeting Grx2/3/4 molecules to the mitochondrial matrix using the Grx5 targeting sequence. The mitochondrial forms of Grx3 and Grx4 partially rescue the defects of a grx5 null mutant. On the contrary, mitochondrially targeted Grx2 does not suppress the mutant phenotype. Both the thioredoxin-like and glutaredoxin domains are needed for the mitochondrial activity of Grx3, although none of the cysteine residues at the thioredoxin-like domain is required for rescue of the grx5 phenotypes. We have concluded that dithiol glutaredoxins are functionally divergent from monothiol ones, but the latter can interchange their biological activities when compartment barriers are surpassed.     

Phylogenetic analysis on genera of Corallobothriinae (Cestoda: Proteocephalidea) from North American ictalurid fishes, using partial sequences of the 28s ribosomal gene

Partial sequences of the 28S rDNA (ribosomal gene) were obtained from a total of 11 populations of 5 species (in 3 genera) of North American corallobothriine proteocephalideans. These included Corallobothrium fimbriatum (3 populations), Corallobothrium parafimbriatum (1 population), Corallotaenia minutia (1 population), Megathylacoides giganteum (2 populations), and Megathylacoides lamothei (4 populations). These sequences were used in a phylogenetic analysis to test the monophyly of Corallobothriinae and to investigate the interrelationships of the North American species. The results indicate that Corallobothriinae, as conventionally understood, is not monophyletic and that only the North American corallobothriines, parasites of ictalurid catfishes, form a monophyletic group. Corallobothrium parafimbriatum is sister taxon to a clade that includes Corallotaenia intermedia and C. minutia and not to its congener C. fimbriatum. Also, M. giganteum from Mexico appears to be more closely related to M. lamothei than to its conspecific in Canada. This and the amount of sequence divergence indicate possible cryptic speciation in its endemic host, the Lerma catfish, Ictalurus dugesi.     

Enzymes that hydrolyze adenine nucleotides of patients with hypercholesterolemia and inflammatory processes

The activity of NTPDase (EC 3.6.1.5, apyrase, CD39) was verified in platelets from patients with increasing cholesterol levels. A possible association between cholesterol levels and inflammatory markers, such as oxidized low-density lipoprotein, highly sensitive C-reactive protein and oxidized low-density lipoprotein autoantibodies, was also investigated. Lipid peroxidation was estimated by measurement of thiobarbituric acid reactive substances in serum. The following groups were studied: group I, < 150 mg.dL(-1) cholesterol; group II, 151-200 mg.dL(-1) cholesterol; group III, 201-250 mg.dL(-1) cholesterol; and group IV, > 251 mg.dL(-1) cholesterol. The results demonstrated that both ATP hydrolysis and ADP hydrolysis were enhanced as a function of cholesterol level. Low-density lipoprotein levels increased concomitantly with total cholesterol levels. Triglyceride levels were increased in the groups with total cholesterol above 251 mg.dL(-1). Oxidized low-density lipoprotein levels were elevated in groups II, III, and IV. Highly sensitive C-reactive protein was elevated in the group with cholesterol levels higher than 251 mg.dL(-1). Oxidized low-density lipoprotein autoantibodies were elevated in groups III and IV. Thiobarbituric acid reactive substance content was enhanced as a function of cholesterol level. In summary, hypercholesterolemia is associated with enhancement of inflammatory response, oxidative stress, and ATP and ADP hydrolysis. The increased ATP and ADP hydrolysis in group IV was confirmed by an increase in CD39 expression on its surface. The increase in CD39 activity is possibly related to a compensatory response to the inflammatory and pro-oxidative state associated with hypercholesterolemia.     

Structural characterization of cold extracted fraction of soluble sulfated polysaccharide from red seaweed Gracilaria birdiae

Water soluble polysaccharide from Gracilaria birdiae cultivated along the northeast coast of Brazil was characterized by infrared (FT-IR) and nuclear magnetic resonance (NMR) spectroscopy. The composition of the polysaccharide in wt% was determined as: β-d-galp (50.3%), 3,6-anhydro--l-galp (40.5%) and --l-galp-6 sulfate (9.2%). The ratio of l/d units (β-d-galp units and 3,6-anhydro--l-galp + -l-galp-6 sulfate) is that of an ideal agarose. The sulfate content calculated by S% accounts for 6.4%. 1D and 2D NMR techniques were employed in order to assign the spin system of polysaccharide without partial degradation. The structure is composed of → 4-3,6-anhydro--l-galp (1 → 3)β-d-galp 1 → segments, with the possibility of a -l-galp unit substituted at the 6-position by sulfate ester.     

Sleep and academic performance in undergraduates: a multi-measure, multi-predictor approach

The present study examined the associations of sleep patterns with multiple measures of academic achievement of undergraduate university students and tested whether sleep variables emerged as significant predictors of subsequent academic performance when other potential predictors, such as class attendance, time devoted to study, and substance use are considered. A sample of 1654 (55% female) full-time undergraduates 17 to 25 yrs of age responded to a self-response questionnaire on sleep, academics, lifestyle, and well-being that was administered at the middle of the semester. In addition to self-reported measures of academic performance, a final grade for each student was collected at the end of the semester. Univariate analyses found that sleep phase, morningness/eveningness preference, sleep deprivation, sleep quality, and sleep irregularity were significantly associated with at least two academic performance measures. Among 15 potential predictors, stepwise multiple regression analysis identified 5 significant predictors of end-of-semester marks: previous academic achievement, class attendance, sufficient sleep, night outings, and sleep quality (R(2)=0.14 and adjusted R(2)=0.14, F(5, 1234)= 40.99, p < .0001). Associations between academic achievement and the remaining sleep variables as well as the academic, well-being, and lifestyle variables lost significance in stepwise regression. Together with class attendance, night outings, and previous academic achievement, self-reported sleep quality and self-reported frequency of sufficient sleep were among the main predictors of academic performance, adding an independent and significant contribution, regardless of academic variables and lifestyles of the students.     

Identifying Hendra virus diversity in pteropid bats

Hendra virus (HeV) causes a zoonotic disease with high mortality that is transmitted to humans from bats of the genus Pteropus (flying foxes) via an intermediary equine host. Factors promoting spillover from bats to horses are uncertain at this time, but plausibly encompass host and/or agent and/or environmental factors. There is a lack of HeV sequence information derived from the natural bat host, as previously sequences have only been obtained from horses or humans following spillover events. In order to obtain an insight into possible variants of HeV circulating in flying foxes, collection of urine was undertaken in multiple flying fox roosts in Queensland, Australia. HeV was found to be geographically widespread in flying foxes with a number of HeV variants circulating at the one time at multiple locations, while at times the same variant was found circulating at disparate locations. Sequence diversity within variants allowed differentiation on the basis of nucleotide changes, and hypervariable regions in the genome were identified that could be used to differentiate circulating variants. Further, during the study, HeV was isolated from the urine of flying foxes on four occasions from three different locations. The data indicates that spillover events do not correlate with particular HeV isolates, suggesting that host and/or environmental factors are the primary determinants of bat-horse spillover. Thus future spillover events are likely to occur, and there is an on-going need for effective risk management strategies for both human and animal health.     

Pandemic influenza due to pH1N1/2009 virus: estimation of infection burden in Reunion Island through a prospective serosurvey, austral winter 2009

Background

To date, there is little information that reflects the true extent of spread of the pH1N1/2009v influenza pandemic at the community level as infection often results in mild or no clinical symptoms. This study aimed at assessing through a prospective study, the attack rate of pH1N1/2009 virus in Reunion Island and risk factors of infection, during the 2009 season.

Methodology/Principal Findings

A serosurvey was conducted during the 2009 austral winter, in the frame of a prospective population study. Pairs of sera were collected from 1687 individuals belonging to 772 households, during and after passage of the pandemic wave. Antibodies to pH1N1/2009v were titered using the hemagglutination inhibition assay (HIA) with titers ≥1/40 being considered positive. Seroprevalence during the first two weeks of detection of pH1N1/2009v in Reunion Island was 29.8% in people under 20 years of age, 35.6% in adults (20–59 years) and 73.3% in the elderly (≥60 years) (P<0.0001). Baseline corrected cumulative incidence rates, were 42.9%, 13.9% and 0% in these age groups respectively (P<0.0001). A significant decline in antibody titers occurred soon after the passage of the epidemic wave. Seroconversion rates to pH1N1/2009 correlated negatively with age: 63.2%, 39.4% and 16.7%, in each age group respectively (P<0.0001). Seroconversion occurred in 65.2% of individuals who were seronegative at inclusion compared to 6.8% in those who were initially seropositive.

Conclusions

Seroincidence of pH1N1/2009v infection was three times that estimated from clinical surveillance, indicating that almost two thirds of infections occurring at the community level have escaped medical detection. People under 20 years of age were the most affected group. Pre-epidemic titers ≥1/40 prevented seroconversion and are likely protective against infection. A concern was raised about the long term stability of the antibody responses.