HnRNP G and Tra2beta: opposite effects on splicing matched by antagonism in RNA binding

The hnRNP G family comprises three closely related proteins, hnRNP G, RBMY and hnRNP G-T. We showed previously that they interact with splicing activator proteins, particularly hTra2beta, and suggested that they were involved in regulating Tra2-dependent splicing. We show here that hnRNP G and hTra2beta have opposite effects upon the incorporation of several exons, both being able to act as either an activator or a repressor. HnRNP G acts via a specific sequence to repress the skeletal muscle-specific exon (SK) of human slow skeletal alpha-tropomyosin, TPM3, and stimulates inclusion of the alternative non-muscle exon. The binding of hnRNP G to the exon is antagonized by hTra2beta. The two proteins also have opposite effects upon a dystrophin pseudo-exon. This exon is incorporated in a patient to a higher level in heart muscle than skeletal muscle, causing X-linked dilated cardiomyopathy. It is included to a higher level after transfection of a mini-gene into rodent cardiac myoblasts than into skeletal muscle myoblasts. Co-transfection with hnRNP G represses incorporation in cardiac myoblasts, whereas hTra2beta increases it in skeletal myoblasts. Both the cell specificity and the protein responses depend upon exon sequences. Since the ratio of hnRNP G to Tra2beta mRNA in humans is higher in skeletal muscle than in heart muscle, we propose that the hnRNP G/Tra2beta ratio contributes to the cellular splicing preferences and that the higher proportion of hnRNP G in skeletal muscle plays a role in preventing the incorporation of the pseudo-exon and thus in preventing skeletal muscle dystrophy.     

Superoxide dismutase activity and the effects of NBQX and CPP on lipid peroxidation in experimental spinal cord injury

The endogenous activity of the neuroprotective enzyme superoxide dismutase (SOD) and the amount of lipid peroxidation in the early phase of experimental spinal cord injury, together with the effects of N-methyl-D-aspartate (NMDA) antagonist CPP and non-NMDA antagonist NBQX on lipid peroxidation were evaluated. The clip compression model was used for the production of a standardized spinal cord trauma. SOD activity and malondialdehyde (MDA) levels — as an indicator of lipid peroxidation — were determined in the injured segment of the spinal cord 30 and 60 min after injury. SOD activity did not change in this period, whereas MDA levels at 30 and 60 min after trauma were significantly elevated. Intrathecal administration of CPP or NBQX 15 min after injury produced statistically significant reductions in MDA elevation 60 min after injury. NBQX was found to be more effective than CPP. These results demonstrated that intrathecal local application of excitatory amino acid receptor antagonists can protect the spinal cord from secondary damage caused by the generation of lipid peroxides in experimental spinal cord injury.     

Positioning of old and new biologicals and small molecules in the treatment of inflammatory bowel diseases

The past decade has brought substantial advances in the management of inflammatory bowel diseases(IBD). The introduction of tumor necrosis factor(TNF) antagonists, evidence for the value of combination therapy, the recog-nition of targeting lymphocyte trafficking and activation as a viable treatment, and the need for early treatment of high-risk patients are all fundamental concepts for current modern IBD treatment algorithms. In this article, authors review the existing data on approved biologicals and small molecules as well as provide insight on the current positioning of approved therapies. Patient stratification for the selection of specific therapies, therapeutic targets and patient monitoring will be discussed as well. The thera-peutic armamentarium for IBD is expanding as novel and more targeted therapies become available. In the absence of comparative trials, positioning these agents is becoming difficult. Emerging concepts for the future will include an emphasis on the development of algorithms which will facilitate a greater understanding of the positioning of novel biological drugs and small molecules in order to best tailor therapy to the patient. In the interim, anti-TNF therapy remains an important component of IBD therapy with the most real-life evidence and should be considered as first-line therapy in patients with complicated Crohn's disease and in acute-severe ulcerative colitis. The safety and efficacy of these ‘older' anti-TNF therapies can be optimized by adhering to therapeutic algorithms which combine clinical and objective markers of disease severityand response to therapy.     

Annular Plaques on the Tongue: What Is Your Diagnosis?

Geographic tongue is an inflammatory disorder of the tongue characterized by asymptomatic erythematous patches with serpiginous borders. Candidiasis of the tongue may be confused with geographic tongue. A 63-year-old male patient with painful white annular lesions localized to the left side of his tongue is presented. He applied topical corticosteroid and antiinflammatory agents, but his lesions did not respond to those therapies. Using direct mycologic examination and culture, the patient was diagnosed with candidiasis. After systemic and topical antifungal therapy, clinical improvement was observed. With this case, the clinical forms of oral candidiasis were discussed, and it was suggested that the clinical presentation of mucosal candidiasis may vary according to the stage of infection and individual immunity.     

Vitamin D Deficiency and Tuberculosis Progression

To assess the association between vitamin D deficiency and tuberculosis disease progression, we studied vitamin D levels in a cohort of tuberculosis patients and their contacts (N = 129) in Pakistan. Most (79%) persons showed deficiency. Low vitamin D levels were associated with a 5-fold increased risk for progression to tuberculosis.     

Clinicopathologic evaluation of subgroups of diffuse large B cell lymphoma by immunohistochemistry

Diffuse large B cell lymphoma (DLBCL) has become an emerging epidemic in recent years. Striking heterogeneity in its clinical, biological and treatment responses prompted us to identify variation in our study group. The aim was to classify the DLBCL into prognosis-based subgroups according to the WHO classification and to evaluate their relation to clinical parameters (age, gender, anatomic location and B symptoms), as well as bcl 2 and Ki 67 status. Patients and Methods: A cross sectional study was carried out on 42 DLBCL patients, classified histologically and immunophenotypically into germinal center B cell like (GCB) or non-GCB type. Immunohistochemistry (IHC) was performed using antibodies against CD 10, MUM-1 and bcl 6; additionally anti-apoptotic protein bcl 2 and proliferative marker Ki 67 (using cutoff value of 70%) were also assayed by IHC. Results: Of the total 27/42 (64%) were males and 15/42 (36%) females, with a mean age of 44.1±15 years. 15/42 (36%) cases were of GCB type as compared to 27/42 (64%) of non GCB type. Extranodal involvement and B symptoms were seen in 18/27 (66.6%) and 20/27(74%) of the non GCB type, whereas bcl 2 protein expression and Ki 67 proliferative index (PI) <70% were each noted in 22/27 (81.4%). Conclusion: We document an astonishingly high number of non-GCB type DLBCL in our population. It is alarming to see such an aggressive tumor proliferating in our region. Significant association of non-GCB type with extranodal origin, B symptoms and low Ki 67 PI (<70%) is another concern.     

Genetic Diversity in the G Protein Gene of Human Respiratory Syncytial Virus among Iranian Children with Acute Respiratory Symptoms

Objective

Acute respiratory infection (ARI) is the major cause of morbidity and mortality in children worldwide. Human respiratory syncytial virus (HRSV) is main viral agent of ARI in infants and young children in terms of effect and prevalence. The aim of this study was to investigate HRSV genotypes during one season in Iran.

Methods

In this cross-sectional study, 107 throat swabs were collected from children less than 5 years of age with acute respiratory infection from October to December 2009. The respiratory samples were obtained from several provinces: Tehran, Isfahan, Hamadan, Zanjan, Kordestan, Lorestan and West Azarbayjan, and were tested for G protein gene of HRSV by RT-PCR.

Findings

Of the 107 respiratory samples, 24 (22.42%) were positive for HRSV, of which 16 (66.6%) belonged to subgroup A and 8 (33.4%) to subgroup B. Phylogenetic analysis revealed that subgroup A strains fell in two genotypes GA1 and GA2, whereas subgroup B strains clustered in genotype BA.

Conclusion

This study revealed that multiple genotypes of HRSV cocirculated during the season 2009 in Iran. Also subgroup A strains were more prevalent than subgroup B strains, and genotype GA1 was predominant during the season.