Retrospective-prospective study of safety and efficacy of sofosbuvir-based direct-acting antivirals in HIV/HCV-coinfected participants with decompensated liver disease pre– or post–liver transplant

Direct-acting antiviral (DAA) therapy has transformed the management of human immunodeficiency virus (HIV) and hepatitis C (HCV) coinfected patients with advanced liver disease. STOP-Coinfection was a multicenter prospective and retrospective, open-label study using sofosbuvir-based DAA therapy to treat HIV/HCV-coinfected participants pre– or post–liver transplant (LT). Sixty-eight participants with end-stage liver disease (Child-Turcotte-Pugh score ≥7 and Model for End-Stage Liver Disease score 6–29) were enrolled, 26 had hepatocellular carcinoma. Forty-two participants were treated pre–LT and 26 post–LT. All participants completed therapy without need for dose reduction or transfusion; eight required two or more courses of therapy. Ninety-three percent achieved a sustained virologic response and DAA therapy was well tolerated. Despite HCV cure, 12 end-stage liver disease participants required subsequent LT, 7 for decompensated liver disease. Thirteen participants died, 10 with decompensated liver disease pre–LT and three post–LT. Overall, transplant free survival was 42.8% at 4 years and post–LT survival was 87.9% at 5 years. We conclude that sofosbuvir-based DAA therapy is safe and highly effective in HCV-HIV patients with decompensated liver disease and post–LT, with post–LT survival rates comparable to other indications. This removes one of the last barriers to liver transplantation in this challenging cohort of recipients.     

A glyceraldehyde-3-phosphate dehydrogenase homolog in Borrelia burgdorferi and Borrelia hermsii.

A polyreactive monoclonal antibody recognized a 38.5-kDa polypeptide with amino-terminal sequence identity to conserved regions of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in Borrelia burgdorferi, the Lyme disease agent, and Borrelia hermsii, an agent of American relapsing fever. This monoclonal antibody also recognized GAPDH from other pathogenic spirochetes and other prokaryotes and eukaryotes as well. GAPDH activity was detected in sonicates of both B. burgdorferi and B. hermsii but not in live, intact organisms, indicating the possibility of a subsurface localization for the Borrelia GAPDH activity. Degenerate primers constructed from highly conserved regions of gapdh of other prokaryotes successfully amplified this gene homolog in both B. burgdorferi and B. hermsii. Nuclei acid and deduced amino acid sequence analysis of the 838-bp probes for each borrelia indicated 93.9% identity between B. burgdorferi and B. hermsii at the amino acid level. Amino acid identities of B. burgdorferi and B. hermsii with Bacillus stearothermophilus were 59.2% and 58.8% respectively. Southern hybridization studies indicated that the gene encoding GAPDH is located on the chromosome of each borrella. In other bacterial species, GAPDH has other functions in addition to its traditional enzymatic role in the glycolytic pathway. GAPDH may play a similar role in borrelias.     

Recovery of motor function after spinal-cord injury--a randomized, placebo-controlled trial with GM-1 ganglioside

BACKGROUND. Spinal-cord injury is devastating; until recently, there was no medical treatment to improve recovery of the initial neurologic deficit. Studies in animals have shown that monosialotetrahexosylganglioside (GM-1) ganglioside enhances the functional recovery of damaged neurons. METHODS. A prospective, randomized, placebo-controlled, double-blind trial of GM-1 ganglioside was conducted in patients with spinal-cord injuries. Of 37 patients entered into the study, 34 (23 with cervical injuries and 11 with thoracic injuries) completed the test-drug protocol (100 mg of GM-1 sodium salt or placebo intravenously per day for 18 to 32 doses, with the first dose taken within 72 hours of the injury) and a one-year follow-up period. Neurologic recovery was assessed with the Frankel scale (comprising five categories) and the American Spinal Injury Association (ASIA) motor score (a scale of scores from 0 to 100, derived from strength tests of 20 specific muscles, each scored from 0 to 5). RESULTS. There was a significant difference between groups in the distribution of improvement of Frankel grades from base line to the one-year follow-up (improvement of 0, 1, 2, and 3 grades in 13, 4, 1, and 0 patients, respectively, in the placebo group and 8, 1, 6, and 1 patients, respectively, in the GM-1 group; P = 0.034 by the Cochran-Mantel-Haenszel chi-square test). The GM-1-treated patients also had a significantly greater mean improvement in ASIA motor score from base line to the one-year follow-up than the placebo-treated patients (36.9 vs. 21.6 points; P = 0.047 by analysis of covariance with the base-line ASIA motor score as the covariate). An analysis of individual muscle recoveries revealed that the increased recovery in the GM-1 group was attributable to initially paralyzed muscles that regained useful motor strength rather than to strengthening of paretic muscles. CONCLUSIONS. This small study provides evidence that GM-1 enhances the recovery of neurologic function after one year. A larger study must be conducted, however, before GM-1 is considered efficacious and safe in treating spinal-cord injury.     

Nasogastric and intravenous infusions of (+)-4-propyl-9-hydroxynaphthoxazine (PHNO) in Parkinson's disease.

(+)-4-propyl-9-hydroxynaphthoxazine (PHNO) is a new dopamine agonist which is capable of producing a sustained response in parkinsonian patients with "on-off" fluctuations when given as a continuous infusion either nasogastrically or intravenously. These data suggest that a sustained release formulation of PHNO may provide a significant, new treatment for patients with "on-off" fluctuations.     

Improved methodology for analyzing local and distant recurrence

Studies of radiation therapy and/or surgery in the treatment of cancer frequently use actuarial methods to estimate curves of time to local failure and compare two such curves with statistical methods originally developed for survival data. In such analyses, patients who fail first in distant sites or die before local failure are considered censored for time to local failure. While the arithmetic of these calculations is usually correct, the interpretation of the results is almost universally incorrect. For example, an actuarial Kaplan-Meier curve of time to breast recurrence after breast conserving treatment consistently overestimates the percentage of patients who would benefit from a subsequent mastectomy. Actuarial methods require the assumption that time to local failure and time to distant failure are statistically independent. For most human malignancies this is not a reasonable assumption, since there are always some patient subgroups at high risk of both local and distant failure and some patient subgroups at low risk for either type of failure. Without the assumption of independence, the time to local failure distribution is not well defined. The basic problem is that estimating time to local failure falls into the category of analyzing "competing risks," since the various causes of failure are competing for the same patient. For this reason, the effects of a particular treatment on local failure cannot be assessed separately from its effects on distant failure. This report explains the concepts of statistical independence, nonidentifiability, and competing risks and illustrates the pitfalls of using actuarial methods to assess local tumor control.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bioactivation of benzocaine to a methaemoglobin-forming metabolite by rat and human microsomes in vitro

Benzocaine-mediated methaemoglobin-generation was compared with that of dapsone in vitro. Direct incubation of benzocaine with washed human erythrocytes alone at up to 15 mM did not result in significant methaemoglobin formation (0.4 ± 0.1%). With rat microsomes, dapsone-dependent methaemoglobin formation was almost two-fold that of benzocaine at 30 min (56.5 ± 0.7% vs 31.6 ± 2.4% P < 0.005)). Benzocaine-mediated methaemoglobin formation was significantly reduced in the presence of DDC (diethyldithiocarbamate) at the 10 (P < 0.005) and 20 (P < 0.025) min time points. At 30 min, cimetidine reduced benzocaine-mediated methaemoglobin from 34.4 ± 8.7% to less than 3% (P < 0.005). The methaemoglobin forming capacity of dapsone was significantly inhibited at all three time points by both DDC (P < 0.005) and cimetidine (P < 0.005). Incubation of benzocaine with microsomes from five human livers showed that each liver produced methaemoglobin-forming metabolites. No inhibitory effect was seen with DDC, although cimetidine caused a significant reduction (32.8 ± 12.4% overall) in benzocaine-mediated methaemoglobin formation in the four livers tested.     

Gangliogliomas: characterization by registered positron emission tomography-MR images

OBJECTIVE: The purpose of this study was to correlate 18F-fluorodeoxyglucose positron emission tomography (PET) and MR imaging features of cerebral gangliogliomas before and after PET-MR image registration. CONCLUSION: After registration of PET and MR images, all six gangliogliomas in our series were shown to have heterogeneous metabolic activity. Areas of hypermetabolic activity were seen in all lesions. In five of the six cases, PET-MR image registration provided information regarding tumor metabolism that was not available on nonregistered hard-copy examinations.