mTOR pathway activation in large vessel vasculitis.

BACKGROUND: Mammalian target of rapamycin complex 1 (mTORC 1) drives the proinflammatory expansion of T helper (TH) type 1, TH17 cells and controls fibroblast proliferation, typical features of large vessel vasculitis (LVV) pathogenesis. Molecular pathways involved in arterial lesions of LVV are unknown. METHODS: We evaluate mTORC pathway activation in vascular aorta lesions and in T cell homeostasis of patients with LVV. RESULTS: Proliferation of both endothelial cells and vascular smooth-muscle cells was shown in vascular lesions in LVV. The vascular endothelium of proliferating aorta vessels from patients with LVV showed indications of activation of the mTORC1 pathway (S6RP phosphorylation). In cultured vascular endothelial cells, sera from patients with LVV stimulated mTORC1 through the phosphorylation of S6RP. mTORC1 activation was found also in Th1 and Th17 cells both systemically and in inflamed vessels. Patients with LVV exhibited a diminished S6RP phosphorylation in Tregs. Inhibition of mTORC1 pathway with rapamycin, increase Tregs and decrease effector CD4+IFNγ+, CD4+IL17+ and CD4+IL21+ T cells in patients with LVV. CONCLUSIONS: We provided evidence that mTORC1 pathway has a central role in driving T cell inflammation and vascular lesions in LVV. Targeting mTORC pathway may represent a new therapeutic option in patients with LVV.

Recurrent 2,8-dihydroxyadenine nephropathy: a rare but preventable cause of renal allograft failure.

Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive enzyme defect of purine metabolism that usually manifests as 2,8-dihydroxyadenine (2,8-DHA) nephrolithiasis and more rarely chronic kidney disease. The disease is most often misdiagnosed and can recur in the renal allograft. We analyzed nine patients with recurrent 2,8-DHA crystalline nephropathy, in all of whom the diagnosis had been missed prior to renal transplantation. The diagnosis was established at a median of 5 (range 1.5-312) weeks following the transplant procedure. Patients had delayed graft function (n=2), acute-on-chronic (n=5) or acute (n=1) allograft dysfunction, whereas one patient had normal graft function at the time of diagnosis. Analysis of allograft biopsies showed birefringent 2,8-DHA crystals in renal tubular lumens, within tubular epithelial cells and interstitium. Fourier transformed infrared microscopy confirmed the diagnosis in all cases, which was further supported by 2,8-DHA crystalluria, undetectable erythrocyte APRT enzyme activity, and genetic testing. With allopurinol therapy, the allograft function improved (n=7), remained stable (n=1) or worsened (n=1). At last follow-up, two patients had experienced allograft loss and five had persistent chronic allograft dysfunction. 2,8-DHA nephropathy is a rare but underdiagnosed and preventable disorder that can recur in the renal allograft and may lead to allograft loss.

Assessment of urinary iodine excretion among normal Kuwaiti adults.

This study was performed to investigate the status of iodine intake among the Kuwaiti population and its effect on thyroid function. The study group was comprised of 139 females and 86 males with a mean age of 33 and 35 years, respectively. Urinary iodine excretion (UIE) and serum free T4 (FT4), thyrotropin hormone (TSH), antiperoxidase antibodies (anti- TPOAb), and antithyroglobulin antibodies (anti-TGAb) were determined. Median UIE was 148 µg/L (within the recommended level by the World Health Organization [WHO]). However, UIE levels of <100 and <50 µg/L were detected in both male and female groups, respectively. Serum levels of TSH and FT4 were normal for all except one of the participants who suffered from hyperthyroidism, possibly as a result of elevated iodine intake, which was reflected in an increased UIE of 590 µg/L. Elevated anti-TPOAb >75 IU/mL and anti-TGAb >150 IU/mL were detected in 15% and 34% of subjects; only 10% of them had elevated levels of both anti-TPOAb and anti-TGAb. Thus, based on the WHO recommendations, the iodine intake for the Kuwaiti population is adequate. However, it is recommended that a national study be conducted by the appropriate authority in order to eliminate any artifacts which may have appeared in this study.

In vitro screening of five local medicinal plants for antibacterial activity using disc diffusion method.

Medicinal plants have many traditional claims including the treatment of ailments of infectious origin. In the evaluation of traditional claims, scientific research is important. The objective of the study was to determine the presence of antibacterial activity in the crude extracts of some of the commonly used medicinal plants in Malaysia, Andrographis paniculata, Vitex negundo, Morinda citrifolia, Piper sarmentosum, and Centella asiatica. In this preliminary investigation, the leaves were used and the crude extracts were subjected to screening against five strains of bacteria species, Methicillin Resistant Staphylococcus aureus (MRSA), Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli, using standard protocol of Disc Diffusion Method (DDM). The antibacterial activities were assessed by the presence or absence of inhibition zones and MIC values. M. citrifolia, P. sarmentosum and C. asiatica methanol extract and A. paniculata (water extract) have potential antibacterial activities to both gram positive S. aureus and Methicillin Resistant S. aureus (MRSA). None of the five plant extracts tested showed antibacterial activities to gram negative E. coli and K. pneumoniae, except for A. paniculata and P. sarmentosum which showed activity towards P. aeruginosa. A. paniculata being the most potent at MIC of 2 g/disc. This finding forms a basis for further studies on screening of local medicinal plant extracts for antibacteria properties.