Tryptophan tolerance and metabolism in endogenous depression

The concentration of free and total tryptophan and kynurenine in plasma from 49 female depressives and 26 female controls was measured following oral loading with l-tryptophan, 100 mg/kg body weight. There was no significant difference between five depressives and six controls in the area under curve for free or total tryptophan or kynurenine in plasma. The peak concentration of kynurenine occured 4 h after loading and it correlated significantly with the area under curve for kynurenine. There was no significant correlation between the l-tryptophan dose (g) and the plasma concentration of kynurenine at 4 h in the 49 depressives or 26 controls. The mean plasma levels of tryptophan and kynurenine at 4 h in the depressives were not significantly different from control levels. There was no clear relationship between the plasma levels of tryptophan or kynurenine at 4 h and the therapeutic response in 13 depressives treated with l-tryptophan for 14 days.It is concluded that the absorption, the plasma clearance, and the degradation to kynurenine of loading doses of l-tryptophan are normal in depressed patients. Results further-more suggest that the plasma levels of tryptophan and kynurenine at 4 h are poor predictors of the response to l-tryptophan treatment in depressives.     

An evaluation of interleukin genes fails to identify clear susceptibility loci for multiple sclerosis

Differential expression of interleukins may influence susceptibility to inflammatory diseases such as MS. IL-1a production is increased in MS patients during acute relapse, IL-2 receptor (IL-2R) secretion correlates with disease activity in several inflammatory disorders and is variable in MS. Both IL-4 and IL-10 expression vary significantly with relapse/remission in MS and IL-9 is postulated to inhibit steroid-induced apoptosis. To examine the influence of interleukin (IL) genes on MS susceptibility and clinical course, gene association studies using separate polymorphic microsatellite markers for il-1 alpha, il-2, il-2r beta, il-4 il-9 and il-10 were performed, incorporating 150-177 relapsing-remitting or secondary progressive MS (RR/SPMS) patients, 100-110 primary progressive (PPMS) patients and 152-210 controls. No significant differences existed in allele frequencies between either MS group and controls for any of the interleukin microsatellite markers studied, nor were statistically significant differences observed in PPMS vs. RR/SPMS for any marker. These data indicate that the IL-1 alpha, IL-2, IL-2R beta, IL-4, IL-9 and IL-10 genes are unlikely to be susceptibility loci for MS in this population.     

Synergistic activity of recombinant human endostatin in combination with adriamycin: analysis of in vitro activity on endothelial cells and in vivo tumor progression in an orthotopic murine mammary carcinoma model.

PURPOSE: Current combination treatment strategies in malignancy are designed to evaluate the use of cytotoxic drugs and antiangiogenic agents. Endostatin, a fragment of collagen XVIII, specifically inhibits proliferation, migration, and differentiation of endothelial cells in vitro as well as angiogenesis and tumor progression in in vivo models. In this study, we determine the antitumor effect of rhEndostatin administered alone or in combination with Adriamycin against established orthotopic murine mammary carcinoma. EXPERIMENTAL DESIGN: Mice bearing orthotopically established DA-3 mammary adenocarcinoma tumors received varying doses of rhEndostatin alone and in combination with Adriamycin to assess tumor growth inhibition. Additional studies of this in vivo combination included a determination of Adriamycin-induced cardiotoxicity and in vitro effects on human umbilical vein endothelial cell proliferation and cord formation. RESULTS: For single-agent activity, optimal tumor growth inhibition was observed after s.c. administration of 50 mg/kg/day rhEndostatin or 5 mg/kg Adriamycin injected i.v. every 4 days. Combination of Adriamycin with optimal or suboptimal doses of rhEndostatin resulted in synergistic inhibition of DA-3 tumor growth. Importantly, unlike other antiangiogenic agents, rhEndostatin did not exacerbate the cardiotoxicity of Adriamycin. The synergistic interaction between rhEndostatin and Adriamycin was also observed in vitro for inhibition of human umbilical vein endothelial cell proliferation and inhibition of cord formation. CONCLUSIONS: These data suggest that the synergy observed with rhEndostatin in combination with Adriamycin is exerted at the level of the endothelial cell and can result in enhanced tumor growth inhibition. The potential benefit of Adriamycin used in combination with rhEndostatin is being considered for clinical evaluation.     

The efficacy of the ketogenic diet-1998: a prospective evaluation of intervention in 150 children

OBJECTIVE: The ketogenic diet is a high-fat, low-protein, low-carbohydrate diet developed in the 1920s for the treatment of children with difficult to control seizures. Despite advances in both the pharmacotherapy and the surgery of epilepsy, many children continue to have difficult-to-control seizures. This prospective study sought to determine the ketogenic diet's effectiveness and tolerability in children refractory to today's medications. METHODS: One hundred fifty consecutive children, ages 1 to 16 years, virtually all of whom continued to have more than two seizures per week despite adequate therapy with at least two anticonvulsant medications, were prospectively enrolled in this study, treated with the ketogenic diet, and followed for a minimum of 1 year. Seizure frequency was tabulated from patients' daily seizure calendars and seizure reduction calculated as percentage of baseline frequency. Adverse events and reasons for diet discontinuation were recorded. RESULTS: The children (mean age, 5.3 years), averaged 410 seizures per month before the diet, despite an exposure to a mean of 6.2 antiepileptic medications. Three months after diet initiation, 83% of those starting remained on the diet and 34% had >90% decrease in seizures. At 6 months, 71% still remained on the diet and 32% had a >90% decrease in seizures. At 1 year, 55% remained on the diet and 27% had a >90% decrease in seizure frequency. Most of those discontinuing the diet did so because it was either insufficiently effective or too restrictive. Seven percent stopped because of intercurrent illness. CONCLUSIONS: The ketogenic diet should be considered as alternative therapy for children with difficult-to-control seizures. It is more effective than many of the new anticonvulsant medications and is well tolerated by children and families when it is effective.