Predicting durability of a disease resistance gene based on an assessment of the fitness loss and epidemiological consequences of avirulence gene mutation

Durability of plant disease resistance (R) genes may be predicted if the cost of pathogen adaptation to overcome resistance is understood. Adaptation of the bacterial blight pathogen, Xanthomonas oryzae pv. oryzae (Xoo), to virulence in rice is the result of the loss of pathogen avirulence gene function, but little is known about its effect on aggressiveness under field conditions. We evaluated the cost in pathogenic fitness (aggressiveness and persistence) associated with adaptation of Xoo to virulence on near-isogenic rice lines with single R genes (Xa7, Xa10, and Xa4) at two field sites endemic for bacterial blight. Disease severity was high in all 3 years on all lines except the line with Xa7. Of two Xoo lineages (groups of strains inferred to be clonally related based on DNA fingerprinting) detected, one, lineage C, dominated the pathogen population at both sites. All Xoo strains were virulent to Xa4, whereas only lineage C strains were virulent to Xa10. Only a few strains of lineage C were virulent to Xa7. Adaptation to virulence on Xa7 occurred through at least four different pathways and was associated with a reduction in aggressiveness. Loss of avirulence and reduced aggressiveness were associated with mutations at the 3' terminus of the avrXa7 allele. Strains most aggressive to Xa7 were not detected after the second year, suggesting they were less persistent than less aggressive strains. These experiments support the prediction that Xa7 would be a durable R gene because of a fitness penalty in Xoo associated with adaptation to Xa7.     

Safety and efficacy of generic cyclosporine arpimune in Filipino low-risk primary kidney transplant recipients

Background

In the Philippines, maintenance of immunosuppression may not always be affordable, leading to acute rejection and graft loss. The availability of the generic cyclosporine Arpimune could be economically beneficial, but its safety and efficacy should be established.

Methods

This prospective cohort study enrolled 30 renal transplant patients who received Arpimune with mycophenolate/prednisone. Their results were compared up to 6 months with 30 matched control patients who received Neoral during the same period. Areas under the receiver operating characteristic curves (AUC) after intake of Arpimune and therapeutic drug monitoring using cyclosporine levels 2 hours after each dose were done. Pearson correlation was performed to determine linearity of relationship between the generic cyclosporine concentrations and AUC 0-4. Chi-square test was used in obtaining cyclosporine Arpimune concentrations.

Results

The abbreviated concentration AUC of Arpimune was similar to that of Neoral, and the 2-hour sampling point (r = 0.813; P < .001) showed the best correlation. Calculated creatinine clearance (mL/min) versus Neoral was 71.36 ± 13 versus 68.03 ± 16.6 (P = .61) at 1 month, 70.4 ± 14.8 versus 64.2 ± 11.4 (P = .12) at 3 months, and 74.02 ± 15.8 versus 62.03 ± 12.1 (P = .002) at 6 months. Two Arpimune versus 4 Neoral patients (P = .67) developed biopsy-proven acute rejection. One septic death occurred in the Arpimune group. Graft survival was 100% in both groups. Hyperlipidemia was the most frequent side effect for both.

Conclusions

The AUC of Arpimune was similar to that of Neoral. Use of the generic cyclosporine Arpimune provided effective immunosuppression in the 6 months after transplantation. Renal allograft function was similar to that of Neoral, with minimal rates of acute rejection and adverse events.     

Inhibition of Hepatitis C Virus Replication by GS-6620, a Potent C-Nucleoside Monophosphate Prodrug

As a class, nucleotide inhibitors (NIs) of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase offer advantages over other direct-acting antivirals, including properties, such as pangenotype activity, a high barrier to resistance, and reduced potential for drug-drug interactions. We studied the in vitro pharmacology of a novel C-nucleoside adenosine analog monophosphate prodrug, GS-6620. It was found to be a potent and selective HCV inhibitor against HCV replicons of genotypes 1 to 6 and against an infectious genotype 2a virus (50% effective concentration [EC₅₀], 0.048 to 0.68 μM). GS-6620 showed limited activities against other viruses, maintaining only some of its activity against the closely related bovine viral diarrhea virus (EC₅₀, 1.5 μM). The active 5′-triphosphate metabolite of GS-6620 is a chain terminator of viral RNA synthesis and a competitive inhibitor of NS5B-catalyzed ATP incorporation, with K_i/K_m values of 0.23 and 0.18 for HCV NS5B genotypes 1b and 2a, respectively. With its unique dual substitutions of 1′-CN and 2′-C-Me on the ribose ring, the active triphosphate metabolite was found to have enhanced selectivity for the HCV NS5B polymerase over host RNA polymerases. GS-6620 demonstrated a high barrier to resistance in vitro. Prolonged passaging resulted in the selection of the S282T mutation in NS5B that was found to be resistant in both cellular and enzymatic assays (>30-fold). Consistent with its in vitro profile, GS-6620 exhibited the potential for potent anti-HCV activity in a proof-of-concept clinical trial, but its utility was limited by the requirement of high dose levels and pharmacokinetic and pharmacodynamic variability.     

Group Well-Child Care and Health Services Utilization: A Bilingual Qualitative Analysis of Parents’ Perspectives

Maternal and Child Health Journal - Objective Alternative primary care structures such as group well-child care (GWCC) may enhance care for families, particularly those subject to structural...