Chitosan oligosaccharides in combination with Agaricus blazei Murill extract reduces hepatoma formation in mice with severe combined immunodeficiency.

Chitosan and Agaricus blazei Murill (ABM) extracts possess antitumor activities. The aim of the present study was to investigate whether chitosan, ABM extract or the two in combination were effective against tumors in tumor­bearing mice. The mice were subcutaneously injected with SK-Hep 1 cells and were then were divided into the following six groups: Group 1, control group; group 2, chitosan 5 mg/kg/day; group 3, chitosan 20 mg/kg/day; group 4, ABM (246 mg/kg/day) and chitosan (5 mg/kg/day) combined; group 5, ABM (984 mg/kg/day) and chitosan (20 mg/kg/day) combined; and group 6, ABM (984 mg/kg/day). The mice were treated with the different concentrations of chitosan, ABM or combinations of the two for 6 weeks. The levels of glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT) and vascular endothelial growth factor (VEGF), and tissue histopathological features were examined in the surviving animals. Based on the results of the investigation, the treatments performed in groups 2, 3 and 4 were identified as being capable of reducing the weights of the tumors, however, group 4, which was treated with chitosan (5 mg/kg/day) in combination with ABM (246 mg/kg/day) was able to reduce the levels of GOT and VEGF. As a result, treatment with chitosan in combination with ABM may offer potential in cancer therapy and requires further investigation.

Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment.

In the folate cycle MTHFD1, encoded by MTHFD1, is a trifunctional enzyme containing 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase activity. To date, only one patient with MTHFD1 deficiency, presenting with hyperhomocysteinemia, megaloblastic anaemia, hemolytic uremic syndrome (HUS) and severe combined immunodeficiency, has been identified (Watkins et al J Med Genet 48:590-2, 2011). We now describe four additional patients from two different families. The second patient presented with hyperhomocysteinemia, megaloblastic anaemia, HUS, microangiopathy and retinopathy; all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid. The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia, and was successfully treated with a regime that included and was eventually reduced to folic acid. The other two, elder siblings of the third patient, died at 9 weeks of age with megaloblastic anaemia, infection and severe acidosis and had MTFHD1 deficiency diagnosed retrospectively. We identified a missense mutation (c.806C > T, p.Thr296Ile) and a splice site mutation (c.1674G > A) leading to exon skipping in the second patient, while the other three harboured a missense mutation (c.146C > T, p.Ser49Phe) and a premature stop mutation (c.673G > T, p.Glu225*), all of which were novel. Patient fibroblast studies revealed severely reduced methionine formation from [(14)C]-formate, which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid. These additional cases increase the clinical spectrum of this intriguing defect, provide in vitro evidence of disturbed methionine synthesis and substantiate the effectiveness of folic or folinic acid treatment.

Immunodeficiency disorders in horses.

Immunodeficiencies are characterized as primary (genetic) or secondary (acquired). Primary immunodeficiencies are relatively uncommon; however, clinically, they present a significant challenge to the practitioner, especially if the underlying disorder goes unrecognized. Secondary immunodeficiencies may present at any age, but failure of passive transfer in neonatal foals is most commonly encountered. This article provides a general overview of clinical signs and diagnosis of primary and secondary immunodeficiencies currently recognized in horses.

Combined immunodeficiency associated with increased apoptosis of lymphocytes and radiosensitivity fibroblasts.

Severe immunodeficiency characterized by lymphopenia was found in two siblings, one of whom was examined in detail. The calcium flux, pattern of tyrosine phosphorylation of proteins, and interleukin 2 (IL-2) production and proliferation in response to mitogens suggested that the peripheral blood T cells activated normally. The peripheral blood T cells were shown to have an activated phenotype with increased expression of CD45RO+ and CD95/Fas. Increased spontaneous apoptosis occurred in unstimulated lymphocyte cultures. The elevated apoptosis was not due to alterations in expression or to mutations in Bcl-2, Bcl-X(L), or Flip, nor could the spontaneous apoptosis be prevented by blocking Fas, suggesting that it was independent of Fas signaling. This is the first inherited combined immunodeficiency associated with impaired lymphocyte survival. Fibroblasts derived from the patient showed appreciable radiosensitivity in clonal assays, but apoptosis was not elevated. Our results show that the fibroblasts represent a new radiosensitive phenotype not associated with cell cycle checkpoint defects, V(D)J recombination defects, or elevated chromosome breakage. We suggest that the affected gene plays a role in an undetermined damage response mechanism that results in elevated spontaneous apoptosis in lymphoid cells and radiosensitivity in fibroblasts.