Fc-Silent Anti-CD154 Domain Antibody Effectively Prevents Nonhuman Primate Renal Allograft Rejection.

The advent of costimulation blockade provides the prospect for targeted therapy with improved graft survival in transplant patients. Perhaps the most effective costimulation blockade in experimental models is the use of reagents to block the CD40/CD154 pathway. Unfortunately, successful clinical translation of anti-CD154 therapy has not been achieved. In an attempt to develop an agent that is as effective as previous CD154 blocking antibodies but lacks the risk of thromboembolism, we evaluated the efficacy and safety of a novel anti-human CD154 domain antibody (dAb, BMS-986004). The anti-CD154 dAb effectively blocked CD40-CD154 interactions but lacked crystallizable fragment (Fc) binding activity and resultant platelet activation. In a nonhuman primate kidney transplant model, anti-CD154 dAb was safe and efficacious, significantly prolonging allograft survival without evidence of thromboembolism (Median survival time 103 days). The combination of anti-CD154 dAb and conventional immunosuppression synergized to effectively control allograft rejection (Median survival time 397 days). Furthermore, anti-CD154 dAb treatment increased the frequency of CD4+ CD25+ Foxp3+ regulatory T cells. This study demonstrates that the use of a novel anti-CD154 dAb that lacks Fc binding activity is safe without evidence of thromboembolism and is equally as potent as previous anti-CD154 agents at prolonging renal allograft survival in a nonhuman primate preclinical model.

Mechanism of fluconazole resistance in Candida krusei.

The mechanisms of fluconazole resistance in three clinical isolates of Candida krusei were investigated. Analysis of sterols of organisms grown in the absence and presence of fluconazole demonstrated that the predominant sterol of C. krusei is ergosterol and that fluconazole inhibits 14alpha-demethylase in this organism. The 14alpha-demethylase activity in cell extracts of C. krusei was 16- to 46-fold more resistant to inhibition by fluconazole than was 14alpha-demethylase activity in cell extracts of two fluconazole-susceptible strains of Candida albicans. Comparing the carbon monoxide difference spectra of microsomes from C. krusei with those of microsomes from C. albicans indicated that the total cytochrome P-450 content of C. krusei is similar to that of C. albicans. The Soret absorption maximum in these spectra was located at 448 nm for C. krusei and at 450 nm for C. albicans. Finally, the fluconazole accumulation of two of the C. krusei isolates was similar to if not greater than that of C. albicans. Thus, there are significant qualitative differences between the 14alpha-demethylase of C. albicans and C. krusei. In addition, fluconazole resistance in these strains of C. krusei appears to be mediated predominantly by a reduced susceptibility of 14alpha-demethylase to inhibition by this drug.

Erosive adenomatosis of the nipple.

Erosive adenomatosis of the nipple is a benign lesion that clinically mimics Paget's disease of the nipple but has the histologic features of syringocystadenoma papilliferum. Some cases have been mistaken for intraductal papilloma or well-differentiated adenocarcinoma, and unnecessary mastectomies have been performed. Recognition of this lesion is important because it is benign and conservative excision is curative.

D-propranolol and DL-propranolol both decrease conversion of L-thyroxine to L-triiodothyronine.

The effects of propranolol (DL-propranolol) and D-propranolol on thyroid hormone metabolism were studied in six euthyroid volunteers receiving L-thyroxine (T4) and six hypothyroid patients receiving T4 replacement. D-propranolol as well as propranolol decreased L-triiodothyronine (T3) concentrations and the ratio of T3 to T4 in the euthyroid subjects, and D-propranolol decreased these variables in the subjects with hypothyroidism (propranolol was not given to this group). It is concluded from this study and from parallel invitro investigations that the effect of propranolol on the conversion of T4 to T3 is unrelated to its beta-adrenergic blocking activity, and that at low therapeutic doses propranolol may exert appreciable "membrane-stabilising" effects in vivo.

Diabetes mellitus in urban and rural communities in Papua New Guinea. Studies of prevalence and plasma insulin.

Oral glucose tolerance tests (75 g) in 185 urban residents of Port Moresby and 105 ethnically similar rural villagers showed that 15.8% of urban residents had diabetes mellitus (two hour plasma glucose > 11.0 mmol/l and a total of 22% were glucose intolerant (plasma glucose > 9.0 mmol/l), compared with 1.0% and 5.5% in rural people. - Urban men and women were significantly fatter than rural people, but within each population glucose tolerance was not significantly related to weight or to age, although the numbers of old people studied were small. Compared to Australians the Papua New Guinea subjects had a higher fasting plasma insulin (16.5 vs 10.7 microU/ml, p = < 0.05); independent of weight fasting plasma insulin was significantly higher in the rural than urban people studied. After the glucose load, plasma insulin and glucose levels were positively correlated in rural people. In contrast, for the urban group the relation best fitted a quadratic function, with decline in plasma insulin at high levels of glucose. - The prevalence of diabetes in urbanised Melanesians in Papua New Guinea appears similar to other South Pacific countries.

The role of a normal lens in Wolffian lens regeneration.

The mid-ventral third of the iris was excised from 61 adult Notophthalmus viridescens hosts, and the mid-dorsal third of the iris from donor eyes was implanted in its place. After the iris healed and the host lens was removed, two lens regenerates developed, one from the host and one from the transplanted iris. The host regenerate was removed 53-91 days after the first lentectomy. Animals were sacrificed 1-40 days after the second lentectomy. A lens developed from the host dorsal iris IN THE PRESENCE OF A NORMAL REGENERATED LENS IN 75% OF THE CASES. A large space was present between the transplant derived lens and host iris for approximately 20 days after the removal of the host lens at lentectomy 2. Stimulatory factor(s) from the neural retina could reach the competent iris through this space, inducing it to regenerate a lens. Therefore, contact between the normal lens and iris probably acts to prevent lens regeneration. In other experiments, variable amounts of neural retina from either adult or larval donors were implanted into the anterior chamber of adult newt eyes in which the lens, iris and neural retina remained in their normal relationships. Implants also contained dorsal iris, ventral iris, or no iris at all. Competent iris tissue, stimulated by the implanted retina, showed only early stages of lens regeneration, but larval retina effected a greater response than adult retina. This limited response may result from the small amount of retina in the implant, a deficiency in retinal stimulus, or a competition for the retinal factor(s) by competent iris tissues.