A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection

Amorphic mutations in the recombination activating genes RAG1 and RAG2 have been reported to cause T- B- SCID, whereas hypomorphic mutations led to the expansion of a few autoimmune T cell clones responsible for the Omenn syndrome phenotype. We report here a novel clinical and immunological phenotype associated with recessive RAG1 hypomorphic mutations in 4 patients from 4 different families. The immunological phenotype consists of the oligoclonal expansion of TCR gammadelta T cells combined with TCR alphabeta T cell lymphopenia. The clinical phenotype consists of severe, disseminated CMV infection and autoimmune blood cell manifestations. Repertoire studies suggest that CMV infection, in the setting of this particular T cell immunodeficiency, may have driven the TCR gammadelta T cell clonal expansion. This observation extends the range of clinical and immunological phenotypes associated with RAG mutations, emphasizing the role of the genetic background and microbial environment in determining disease phenotype.     

Hematopoietic stem cell transplantation for CD40 ligand deficiency: Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study

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Hepatitis caused by clometacin (Dupéran). Retrospective study of 30 cases. A model of autoimmune drug-induced hepatitis?

Thirty cases of clometacin-induced hepatitis were retrospectively collected over a nine-year period in hepatogastroenterological units of non university, public hospitals. There was a strong female predominance (90 percent). Clometacin (Dupéran) was taken because of arthritis in 8 out of 10 cases. Administration was continuous in 85 percent of cases and median duration was 445 days. median dose was 450 mg per day. Jaundice, fatigue, and weight loss were the most frequent symptoms, but edema, ascites and palmar erythema were not uncommon. Thrombopenia (38 percent) was the most frequent hematologic abnormality. Renal failure, always with benign course, was present in 1/4 of cases. Biochemical disorders indicated hepatocellular and cholestatic hepatitis in 3/4 and 1/4 of cases respectively. Hypoprothrombinemia below 50 percent was noted in 1 out of 6 cases, and was associated with death in half cases. Gamma-globulins were increased in 80 percent of cases, with a predominant increase of IgG. Antinuclear or anti-smooth muscle antibodies were present in 60 percent of cases, whereas antimitochondrial and antimicrosomes were absent. Histopathological examination of the liver biopsy specimens obtained in 25 patients showed acute hepatitis in 8 and chronic active hepatitis with fibrosis in 17--including 6 patients with cirrhosis; there were no epidemiological, clinical (except ascites), or biochemical differences between these two groups. Four of the 7 patients tested had HLA B8 antigens; they all had chronic active hepatitis, with autoantibodies in 3 cases. Median duration of hospitalization was 21 days. Hepatitis was directly responsible for death in 3 patients; biochemical sequelae (hypergammaglobulinemia or anicteric cholestasis) were present in 8 patients, 2 of whom most likely had cirrhosis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Flavonoids in Scutellaria immaculata and S. ramosissima (Lamiaceae) and their biological activity

Objectives The aim of this study was to investigate the flavonoid composition of Scutellaria immaculata and S. ramosissima (Lamiaceae) and the in‐vitro biological activity of their extracts and flavonoids. Methods The flavonoid composition of S. immaculata (Si) and S. ramosissima (Sr) were analysed using LC‐MS. Antimicrobial activity was studied in vitro against a range of bacteria and fungi using diffusion and microdilution methods. Anti‐trypanosomal and cell proliferation inhibitory activity of the extracts and flavonoids was assessed using MTT. The antioxidant activity of the flavonoids and extracts were evaluated using DPPH* test. Key findings LC‐MS investigation of Si and Sr plants allowed the identification, for the first time, of an additional 9 and 16 flavonoids, respectively. The methanol, chloroform and water extracts from these plants and six flavonoids (scutellarin, chrysin, apigenin, apigenin‐7‐O‐glucoside, cynaroside and pinocembrine) exhibited significant inhibition of cell growth against HeLa, HepG‐2 and MCF‐7 cells. The chloroform extract of Sr showed potent cytotoxic effects with IC50 (drug concentration which resulted in a 50% reduction in cell viability) values of 9.25 ± 1.07 µg/ml, 12.83 ± 1.49 µg/ml and 17.29 ± 1.27 µg/ml, respectively. The highest anti‐trypanosomal effect against T. b. brucei was shown by the chloroform extract of Sr with an IC50 (drug concentration which resulted in a 50% inhibition of the biological activity) of 61 µg/ml. The pure flavonoids showed an IC50 range between 3 and 29 µm , with cynaroside as the most active compound with an IC50 value of 3.961 ± 0.133 µm . The chloroform extract of Sr has potent antimicrobial activity against Streptococcus pyogenes (minimum inhibitory concentration, MIC = 0.03 mg/ml). Pinocembrine exhibited a strong activity against the all bacteria except Escherichia coli and yeasts. Water extracts of Sr and Si exhibited potent antioxidant activity with IC50 values of 5.62 ± 0.51 µg/ml and 3.48 ± 0.02 µg/ml, respectively. Scutellarin exerted stronger antioxidant activity than other flavonoids. Conclusions This is the first study reporting an in‐vitro biological investigation for Si and Sr. Especially the chloroform extract of Sr showed potent anticancer and antimicrobial activity. Cynaroside had a highly selective and strong cytotoxicity against T. b. brucei while showing only mild effects against cancer cells.