Infection-related glomerulonephritis: understanding mechanisms

The epidemiology of infection-related glomerulonephritis is undergoing striking changes, particularly in developed countries. The incidence of acute poststreptococcal glomerulonephritis (PSAGN) is decreasing because of the successful treatment of streptococcal infections. In contrast, because of the emergence of antibiotic-resistant staphylococcus strains, such as methicillin-resistant Staphylococcus aureus (MRSA), the incidence of Staphylococcus aureus infection-associated glomerulonephritis (SAAGN) is on the rise. In this review, we focus on the pathogenesis of PSAGN and SAAGN, but also emphasize the clinical importance of differentiating between two major forms of infection-related glomerulonephritis: postinfectious glomerulonephritis (such as PSAGN) and glomerulonephritis associated with active infection (such as SAAGN).     

Proteoglycan‐induced arthritis and recombinant human proteoglycan aggrecan G1 domain–induced arthritis in BALB/c mice resembling two subtypes of rheumatoid arthritis

Objective

To develop a simplified and relatively inexpensive version of cartilage proteoglycan–induced arthritis (PGIA), an autoimmunity model of rheumatoid arthritis (RA), and to evaluate the extent to which this new model replicates the disease parameters of PGIA and RA.

Methods

Recombinant human G1 domain of human cartilage PG containing “arthritogenic” T cell epitopes was generated in a mammalian expression system and used for immunization of BALB/c mice. The development and progression of arthritis in recombinant human PG G1–immunized mice (designated recombinant human PG G1–induced arthritis [GIA]) was monitored, and disease parameters were compared with those in the parent PGIA model.

Results

GIA strongly resembled PGIA, although the clinical symptoms and immune responses in mice with GIA were more uniform than in those with PGIA. Mice with GIA showed evidence of stronger Th1 and Th17 polarization than those with PGIA, and anti‐mouse PG autoantibodies were produced in different isotype ratios in the 2 models. Rheumatoid factor (RF) and anti–cyclic citrullinated peptide (anti‐CCP) antibodies were detected in both models; however, serum levels of IgG‐RF and anti‐CCP antibodies were different in GIA and PGIA, and both parameters correlated better with disease severity in GIA than in PGIA.

Conclusion

GIA is a novel model of seropositive RA that exhibits all of the characteristics of PGIA. Although the clinical phenotypes are similar, GIA and PGIA are characterized by different autoantibody profiles, and the 2 models may represent 2 subtypes of seropositive RA, in which more than 1 type of autoantibody can be used to monitor disease severity and response to treatment.

     

Increased levels of platelet activation markers are positively associated with carotid wall thickness and other atherosclerotic risk factors in obese patients

The role of platelets in the development of atherosclerosis and obesity-related prothrombotic state is still under investigation. In this cross-sectional cohort study, we measured the levels of different platelet activation markers and evaluated their relationship with carotid intima-media thickness (IMT) along with other atherosclerotic risk factors in obese patients with or without atherosclerotic co-morbidities. We enrolled 154 obese patients, including 98 with either hypertension, type 2 diabetes mellitus or dyslipidaemia, 56 without these co-morbidities and 62 age- and sex-matched healthy controls. Platelet P-selectin expression and the number of platelet-derived microparticles (PMPs) were measured by flow cytometry; soluble P-selectin levels were analysed by ELISA and Thr715Pro P-selectin polymorphism was determined by PCR-RFLP. Carotid IMT was examined by ultrasonography. The levels of platelet activation parameters were significantly elevated in all obese subjects with increased carotid IMT compared to healthy controls. There was no effect of Thr715Pro genotype on soluble P-selectin levels in obese individuals contrary to normal subjects. Significant and positive association was revealed between carotid IMT and platelet P-selectin (p<0.0001), soluble P-selectin (p=0.039) and PMP (p=0.0001) levels. After adjusting for multiple variables, independent association was found between soluble P-selectin and fibrinogen (p=0.007), PMP levels and body mass index (p<0.0001) as well as platelet P-selectin and carotid IMT (p=0.012) plus plasminogen activator inhibitor-1 (p=0.009). In conclusion, P-selectin and PMP levels showed positive associations with abnormal carotid IMT and other risk factors in obesity suggesting a critical role of enhanced platelet reactivity in atherosclerotic wall alteration.     

Comparison of paramyxovirus isolates from snakes, lizards and a tortoise

Previously uncharacterized paramyxovirus (PMV) isolates from four snakes, three lizards and a tortoise were compared based on partial sequences of the L, HN, and U genes. Analysis of the sequences supported the classification of all reptilian PMVs in a separate genus (Ferlavirus) in the subfamily Paramyxovirinae. Within each of the gene segments, the squamatid isolates could be divided into two groups with a sequence divergence of 0.3–15.6% nt (0–6.8% aa) within the groups and 19.5–22.3% nt (5–7.4% aa) between the groups for the L gene, and 0.9–15.4% nt (0–6.9% aa) within the groups and 18.2–22.5% nt (4.4–9.5% aa) between the groups for the HN gene while higher values of 0.4–17.1% nt (0–13.3% aa) within the groups and 28.9–31.3% nt (25.5–27.8% aa) between the groups were found for the U gene. Isolates from lizards were found in both groups. There was no host species specificity in the grouping of the isolates from snakes and lizards. However, the L gene sequence obtained from the tortoise isolate differed significantly from the sequences obtained from the snake and lizard isolates. This isolate showed divergence values of 24.2–27% nt (18.5–20.9% aa) compared to the squamatid sequences. The tortoise isolate clustered together with the other reptilian PMVs, but not into any of the squamatid groups on the phylogenetic tree. It is hypothesized that this chelonian PMV has a more unique genome sequence as neither HN nor U gene parts could be amplified using newly designed consensus nested PCRs.     

Mechanisms of impaired mitochondrial energy metabolism in acute and chronic neurodegenerative disorders

Altered mitochondrial energy metabolism contributes to the pathophysiology of acute brain injury caused by ischemia, trauma, and neurotoxins and by chronic neurodegenerative disorders such as Parkinson's and Huntington's diseases. Although much evidence supports that the electron transport chain dysfunction in these metabolic abnormalities has both genetic and intracellular environmental causes, alternative mechanisms are being explored. These include direct, reversible inhibition of cytochrome oxidase by nitric oxide, release of mitochondrial cytochrome c, oxidative inhibition of mitochondrial matrix dehydrogenases and adenine nucleotide transport, the availability of NAD for dehydrogenase reactions, respiratory uncoupling by activities such as that of the permeability transition pore, and altered mitochondrial structure and intracellular trafficking. This review focuses on the catabolism of neuronal NAD and the release of neuronal mitochondrial NAD as important contributors to metabolic dysfunction. In addition, the relationship between apoptotic signaling cascades and disruption of mitochondrial energy metabolism is considered in light of the fine balance between apoptotic and necrotic neural cell death.     

Predictive model for the outcome of infliximab therapy in Crohn's disease based on apoptotic pharmacogenetic index and clinical predictors

BACKGROUND: Infliximab (IFX) is an effective therapy for refractory luminal and fistulizing Crohn's disease (CD). Predictors of response could improve selection of patients with a higher probability of favorable outcomes and could improve the safety profile. We aimed to develop a predictive model for the response to infliximab in CD. METHODS: Genetic and clinical data collected in a previous pharmacogenetic study of apoptosis genes were analyzed using SAS Enterprise miner modeling software and SPSS 12.0. We proposed a novel apoptotic pharmacogenetic index (API) with a score ranging from 0 (low apoptotic response) to 3 (high apoptotic response) and subsequently developed a decision tree model. RESULTS: Response and remission rates significantly increased with API score (P = 0.005 in the group of patients with luminal CD, P = 0.02 in the group of patients with fistulizing CD). Patients with an API < or = 1 (n = 59) had the lowest response and remission rates in both the luminal CD (50% and 39.5%, respectively) and fistulizing CD (61.9% and 28.6%, respectively) groups, compared to those with an API of 2 (n = 158), whose response and remission rates were 73.8% and 56.1%, respectively, in the luminal CD group and 85.7% and 44.9%, respectively, in the fistulizing CD group; and those with an API of 3 (n = 10), whose response and remission rates were 100% and 85.7%, respectively, in the luminal CD group and 100% and 0% in the fistulizing CD group. Response in patients with an API < or = 1 was significantly influenced by concurrent azathioprine therapy in the luminal CD (21.4% versus 78.9%, P < 0.001) and in the fistulizing CD (46.6% versus 100%, P = 0.04) groups. In patients with an API of 2, we saw an interaction with age older than 40 years and location of disease (response 52.2% versus 83.9%, P = 0.008) in the luminal CD group and with baseline CRP greater than 5 mg/L (73.9% versus 93.9%, P = 0.04) in the fistulizing CD group. CONCLUSIONS: From our newly proposed apoptotic pharmacogenetic index and clinical predictors, we developed a model for prediction of low, medium, and high responses to the first infusion of IFX in patients with CD. Further studies are needed to confirm the hypothesis generated by our study.     

Readministration of adenoviral gene delivery to dopamine neurons

An approach currently being explored as treatment for Parkinson's disease is gene therapy. An important question concerns the duration of transgene expression in dopamine neurons and the issues of vector persistence, neuronal damage and the feasibility of readministering vector to the same neuronal population. We show, using an adenoviral vector expressing the LacZ reporter gene, that transgene expression declined over time but with minimal loss of dopamine neurons or vector DNA. Readministration of vector resulted in low levels of transgene delivery to the neurons. Moreover, the neurons to which vector had already been delivered were unable to transport the retrograde tracer fluorogold. Our findings indicate that transgene expression declined in dopamine neurons despite the persistence of virus, and the capacity to readminister vector to these neurons was limited.