Effects of arginine, S-adenosylmethionine and polyamines on nerve regeneration

Introduction - Axon growth and axon regeneration are complex processes requiring an adequate supply of certain metabolic precursors and nutrients. Material and methods - This article reviews the studies examining some of the processes of protein modification fundamental to both nerve regeneration and to the continuous and adequate supply of specific factors such as arginine, S-adenosylmethionine and polyamines. Results - The process of arginylation notably increases following nerve injury and during subsequent regeneration of the nerve, with the most likelyfunction of arginine-modification of nerve proteins being the degradation of proteins damaged through injury. It appears that defective methyl group metabolism may be one of the leading causes of demyelination, as suggested by the observation of reduced cerebrospinal fluid concentrations of s-adenosylmethionine (SAMe) and 5-methyltetrahydrofolate, the key metabolites in methylation processes, in patients with a reduction in myelination of corticospinal tracts. Polyamine synthesis, which depends strongly on the availability of both SAMe and arginine, markedly increases in neurons soon after an injury. This "polyamine-response" has been found to be essential for the survival ofthe parent neurons after injury to their axons. Polyamines probably exert their effects through involvement in DNA, RNA and protein synthesis, or through post-translational modifications that areindicated as the most relevant events of the "axon reaction." Conclusions - Nerve regeneration requires the presence of arginine, s-adenosylmethionine, and polyamines. Further studies are needed to explore the mechanisms involved in these processes.     

Good Safety Profile and Efficacy of Leucocyte Interferon-α in Combination with Oral Ribavirin in Treatment-Naive Patients with Chronic Hepatitis C

Background: The differential tolerability profile of various interferon (IFN)-α preparations used in combination with ribavirin for the treatment of chronic hepatitis C needs to be elucidated. Approximately 8% of patients receiving recombinant IFNα-2b plus ribavirin discontinue treatment because of adverse events. Human leucocyte IFNα is deemed to have a better safety profile than recombinant IFNα. We therefore compared the safety profile and efficacy of ribavirin combined with leucocyte IFNα or with recombinant IFNα-2b in treatment-naive patients with chronic hepatitis C. Study design: We randomised 423 patients to either leucocyte IFNα 3MU three times weekly plus ribavirin (210 patients) or the same dose of recombinant IFNα-2b plus ribavirin (213 patients). Patients were treated for 24 weeks and followed-up for a further 48 weeks. The primary endpoint was the safety profile of the two therapies; the secondary endpoint was the rate of sustained response. Results: In patients receiving leucocyte IFNα, the total number of adverse events was lower than in the group receiving recombinant IFNα (259 vs 441 patients), and the percentage of patients discontinuing treatment because of adverse events or laboratory abnormalities was significantly reduced (4% vs 11%; p = 0.013). Sustained response was observed in 47% of patients receiving leucocyte IFNα plus ribavirin and in 44% of patients receiving IFNα-2b plus ribavirin. Conclusions: Both therapeutic regimens were effective in inducing a sustained response in naive patients. However, the safety profile of leucocyte IFNα plus ribavirin was more favourable than that observed with the administration of recombinant IFNα-2b plus ribavirin, suggesting that leucocyte IFNα may be an alternative option in patients with reduced tolerability to other IFNs.     

Small intestinal submucosa as a small-caliber venous graft: a novel model for hepatocyte transplantation on synthetic biodegradable polymer scaffolds with direct access to the portal venous system

BACKGROUND/PURPOSE: Hepatotrophic factors in the portal blood are critically important for the survival of heterotopically transplanted hepatocytes. Currently, no model exists for the implantation of hepatocytes on biodegradable polymer scaffolds with direct access to the portal blood. This study investigates the use of small intestinal submucosa (SIS) as a small-caliber venous conduit that may be used for the implantation of tissue-engineered liver. METHODS: SIS was prepared from segments of rat jejunum and implanted as a venous conduit between the portal vein and inferior vena cava in 26 heparinized Lewis rats. Venograms were performed periodically, and the grafts were harvested at various time-points and examined by scanning electron microscopy (SEM) and histology. Von Willebrand Factor (vWF) staining was performed to assess endothelialization. RESULTS: Five rats died of technical complications. Seventeen of 21 rats (81%) maintained patent grafts at the time of death up to 8 weeks. Venograms demonstrated patent grafts at 3 and 8 weeks. SEM results showed a smooth luminal surface with endothelial-like cells by 3 weeks. Histology demonstrated a confluent luminal endothelial monolayer, absence of thrombus, and neovascularization in the SIS graft. VWF staining results were positive, confirming the growth of endothelial cells on the luminal surface. In preliminary studies, implantation of hepatocytes seeded on biodegradable polymer tubes into the SIS graft demonstrated clusters of viable cells after 2 days. CONCLUSIONS: Rat SIS can be prepared readily, maintains high patency as a small-caliber venous graft, and may be a useful model for the transplantation of tissue-engineered liver with access to the portal circulation.     

Pharmacokinetics and metabolism of β-2′-deoxythioguanosine and 6-thioguanine in man

Summary Resistance to the antileukemic agent 6-thioguanine (TG) inevitably develops in animal tumors. However, a new agent, -2-deoxythioguanosine (-TGdR) can overcome TG resistance in animal tumor models and is therefore of potential clinical use. The pharmacokinetics of radiolabeled TG were compared with those of -TGdR in patients with cancer after intravenous administration. [³⁵S]--TGdR (5.4 mg/kg, 200 mg/m², 200 Ci total) was administered to five patients; the radiolabel in the plasma declined with an initial half-life (t_1/2) of 14 min and a terminal t_1/2 of 19.3 h. Within 24 h, 65% of the radiolabel was excreted in the urine. In contrast, after administration of [³⁵S]-6-TG (3.4 mg/kg, 125 mg/m², 200 Ci total) the average initial t_1/2 was 40 min while the terminal phase t_1/2 was 28.9 h. Urinary excretion of the radiolabel was 75% of the dose 24 h after administration. Both thiopurines were rapidly and extensively degraded and excreted as 6-thioxanthine, inorganic sulfate, S-methyl-6 thioxanthine, and 6-thiouric acid in addition to other products. Small amounts of unchanged drug were also excreted. These studies suggest that -TGdR is merely a latent form of TG.Deceased, to whose memory this paper is dedicated     

COVID‐19 in solid organ transplant recipients: Initial report from the US epicenter

Solid organ transplant recipients may be at a high risk for SARS‐CoV‐2 infection and poor associated outcomes. We herein report our initial experience with solid organ transplant recipients with SARS‐CoV‐2 infection at two centers during the first 3 weeks of the outbreak in New York City. Baseline characteristics, clinical presentation, antiviral and immunosuppressive management were compared between patients with mild/moderate and severe disease (defined as ICU admission, intubation or death). Ninety patients were analyzed with a median age of 57 years. Forty‐six were kidney recipients, 17 lung, 13 liver, 9 heart, and 5 dual‐organ transplants. The most common presenting symptoms were fever (70%), cough (59%), and dyspnea (43%). Twenty‐two (24%) had mild, 41 (46%) moderate, and 27 (30%) severe disease. Among the 68 hospitalized patients, 12% required non‐rebreather and 35% required intubation. 91% received hydroxychloroquine, 66% azithromycin, 3% remdesivir, 21% tocilizumab, and 24% bolus steroids. Sixteen patients died (18% overall, 24% of hospitalized, 52% of ICU) and 37 (54%) were discharged. In this initial cohort, transplant recipients with COVID‐19 appear to have more severe outcomes, although testing limitations likely led to undercounting of mild/asymptomatic cases. As this outbreak unfolds, COVID‐19 has the potential to severely impact solid organ transplant recipients.     

The 2019-new coronavirus epidemic: Evidence for virus evolution

There is a worldwide concern about the new coronavirus 2019-nCoV as a global public health threat. In this article, we provide a preliminary evolutionary and molecular epidemiological analysis of this new virus. A phylogenetic tree has been built using the 15 available whole genome sequences of 2019-nCoV, 12 whole genome sequences of 2019-nCoV, and 12 highly similar whole genome sequences available in gene bank (five from the severe acute respiratory syndrome, two from Middle East respiratory syndrome, and five from bat SARS-like coronavirus). Fast unconstrained Bayesian approximation analysis shows that the nucleocapsid and the spike glycoprotein have some sites under positive pressure, whereas homology modeling revealed some molecular and structural differences between the viruses. The phylogenetic tree showed that 2019-nCoV significantly clustered with bat SARS-like coronavirus sequence isolated in 2015, whereas structural analysis revealed mutation in Spike Glycoprotein and nucleocapsid protein. From these results, the new 2019-nCoV is distinct from SARS virus, probably trasmitted from bats after mutation conferring ability to infect humans.     

Effects of crack cocaine on neurocognitive function

Because crack cocaine appears to have a preferential effect on the metabolic and electrophysiological activity of the frontal and temporal regions of the brain (Pascual-Leone et al., 1991a, 1991b; Volkow, 1992), we hypothesized that cognitive measures of those regions would be impaired in crack cocaine users relative to measures in normal volunteers. We used logistic regression to determine the relationship of cocaine usage to neuropsychological test performance. We compared 38 patients with an average of 3.6 (SD = 2.5) years of crack cocaine use and 24.5 (SD = 28.1) days of abstinence to 54 normal volunteers on a battery of neuropsychological tests. Statistical adjustments were made for the effects of age, education, socioeconomic class, and level of depression. Our findings were mixed with regard to purported measures of executive/frontal functioning, with worse performance associated with cocaine usage on the Booklet Categories Test, but better performance associated on others (number of categories on the Wisconsin Card Sorting Test, Controlled Oral Word Association). Cocaine usage was associated with impairment on measures of spatial, but not verbal memory, confrontation naming, and Trail-making Test, Part B, a measure of perceptual-motor speed and cognitive flexibility. In summary, it appears that continuous crack cocaine use produces a dissociative pattern in neuropsychological test performance with improvement on some measures, but deterioration on others. The permanence of these effects remains to be determined with longitudinal studies.