A small but important proportion of patients with myasthenia gravis (MG) are refractory to conventional immunotherapy. We have treated 12 such patients by "rebooting" the immune system with high-dose cyclophosphamide (Hi Cy, 200 mg/kg), which largely eliminates the mature immune system, while leaving hematopoietic precursors intact. The objective of this report is to describe the clinical and immunologic results of Hi Cy treatment of refractory MG. We have followed 12 patients clinically for 1-9 years, and have analyzed their humoral and cellular immunologic parameters. Hi Cy is safe and effective. All but one of the patients experienced dramatic clinical improvement for variable periods from 5 months to 7.5 years, lasting for more than 1 year in seven of the patients. Two patients are still in treatment-free remission at 5.5 and 7.5 years, and five have achieved responsiveness to immunosuppressive agents that were previously ineffective. Hi Cy typically reduced, but did not completely eliminate, antibodies to the autoantigen AChR or to tetanus or diphtheria toxin; re-immunization with tetanus or diphtheria toxoid increased the antibody levels. Despite prior thymectomy, T cell receptor excision circles, generally considered to reflect thymic emigrant T cells, were produced by all patients. Hi Cy treatment results in effective, but often not permanent, remission in most refractory myasthenic patients, suggesting that the immune system is in fact "rebooted," but not "reformatted." We therefore recommend that treatment of refractory MG with Hi Cy be followed with maintenance immunotherapy.

Talaromyces marneffei causes life-threatening opportunistic infections, mainly in Southeast Asia and South China. T. marneffei mainly infects patients with human immunodeficiency virus (HIV) but also infects individuals without known immunosuppression. Here we investigated the involvement of anti–IFN-γ autoantibodies in severe T. marneffei infections in HIV-negative patients. We enrolled 58 HIV-negative adults with severe T. marneffei infections who were otherwise healthy. We found a high prevalence of neutralizing anti–IFN-γ autoantibodies (94.8%) in this cohort. The presence of anti–IFN-γ autoantibodies was strongly associated with HLA-DRB1*16:02 and -DQB1*05:02 alleles in these patients. We demonstrated that adult-onset acquired immunodeficiency due to autoantibodies against IFN-γ is the major cause of severe T. marneffei infections in HIV-negative patients in regions where this fungus is endemic. The high prevalence of anti–IFN-γ autoantibody–associated HLA class II DRB1*16:02 and DQB1*05:02 alleles may account for severe T. marneffei infections in Southeast Asia. Our findings clarify the pathogenesis of T. marneffei infection and pave the way for developing novel treatments.

Aims Long‐term use of the immunosuppressant tacrolimus is limited by nephrotoxicity. Following renal transplantation, the risk of nephrotoxicity may be determined more by allograft than by blood tacrolimus concentrations, and thus may be affected by donor CYP3A5 and ABCB1 genetics. Little is known regarding factors that determine tacrolimus intrarenal exposure. Methods This study investigated the relationship between trough blood (C0Blood) and allograft (CGraft) tacrolimus concentrations and tacrolimus dose, haematocrit, genetics, acute nephrotoxicity, rejection status, delayed graft function, and time post‐transplant. C0Blood and CGraft were quantified in 132 renal transplant recipients together with recipient and donor CYP3A5 (rs776746) and ABCB1 3435 (rs1045642) genotypes. Results C0Blood ranged from 2.6 to 52.3 ng/mL and CGraft from 33 to 828 pg/mg tissue. Adjusting for dose, recipients who were CYP3A5 expressors had lower C0Blood compared to nonexpressors, whilst delayed graft function was associated with higher C0Blood. Linear regression showed that the significant predictors of CGraft were C0Blood (point‐wise P = 7 × 10−10), dose (P = .004) acute nephrotoxicity (P = .002) and an interaction between C0Blood and acute tacrolimus nephrotoxicity (P = .0002), with an adjusted r2 = 0.35 and no contribution from donor or recipient CYP3A5 or ABCB1 genotype. The association between CGraft and acute nephrotoxicity depended on one very high CGraft (828 pg/mg tissue). Conclusions Recipient and donor CYP3A5 and ABCB1 3435C>T genotypes are not determinants of allograft tacrolimus exposure in kidney transplant recipients. However, tacrolimus dose and C0Blood were significant predictors of CGraft, and the relationship between C0Blood and CGraft appeared to differ in the presence or absence of acute nephrotoxicity.

Neurogenic dural vasodilation has been demonstrated to play an important role in migraine. 5-HT(7) receptors have been found on trigeminal nerve endings and middle meningeal arteries and demonstrated involved in the dilatation of meningeal arteries. The aim of the present study was to demonstrate whether 5-HT(7) receptors are involved in neurogenic dural vasodilation in migraine. The neurogenic dural vasodilation model of migraine was used in this study. Unilateral electrical stimulation of dura mater was performed in anesthetized male Sprague-Dawley rats. Animals were pretreated with selective 5-HT(7) receptor agonist AS19, 5-HT(7) receptor antagonist SB269970, 5-HT1B/1D receptor agonist sumatriptan, or vehicles. Blood flow of the middle meningeal artery (MMA) was measured by a laser Doppler flowmetry. AS19 significantly increased the basal and stimulated blood flows of the middle meningeal artery following electrical stimulation of dura mater, and its effect was dose dependent at the early stage. SB269970 and sumatriptan significantly reduced the basal and stimulated blood flows of middle meningeal artery. The present study demonstrates for the first time that 5-HT(7) receptors are involved in neurogenic dural vasodilation evoked by electrical stimulation of dura mater and maybe of relevance in the pathophysiology and treatment of migraine.