Sustained pharmacological depletion of serum amyloid P component in patients with systemic amyloidosis

Serum amyloid P component (SAP) is a universal constituent of amyloid deposits and contributes to their formation and/or persistence. We therefore developed CPHPC ((R)‐1‐[6‐[(R)‐2‐carboxy‐pyrrolidin‐1‐yl]‐6‐oxo‐hexa‐noyl]pyrrolidine‐2 carboxylic acid), a novel bis(D‐proline) drug, to specifically target SAP and report here a first, exploratory, open label proof of principle study in systemic amyloidosis. CPHPC produced sustained, >95% depletion of circulating SAP in all patients and c. 90% reduction in the SAP content of the two amyloidotic organs that became available. There were no significant adverse effects of either SAP depletion or CPHPC itself. No accumulation of amyloid was demonstrable by SAP scintigraphy in any patient on the drug. In hereditary fibrinogen amyloidosis, which is inexorably progressive, proteinuria was reduced in four of five patients receiving CPHPC and renal survival was prolonged compared to a historical control group. These promising clinical observations merit further study.     

Definition of a high-affinity Gag recognition structure mediating packaging of a retroviral RNA genome

All retroviral genomic RNAs contain a cis-acting packaging signal by which dimeric genomes are selectively packaged into nascent virions. However, it is not understood how Gag (the viral structural protein) interacts with these signals to package the genome with high selectivity. We probed the structure of murine leukemia virus RNA inside virus particles using SHAPE, a high-throughput RNA structure analysis technology. These experiments showed that NC (the nucleic acid binding domain derived from Gag) binds within the virus to the sequence UCUG-UR-UCUG. Recombinant Gag and NC proteins bound to this same RNA sequence in dimeric RNA in vitro; in all cases, interactions were strongest with the first U and final G in each UCUG element. The RNA structural context is critical: High-affinity binding requires base-paired regions flanking this motif, and two UCUG-UR-UCUG motifs are specifically exposed in the viral RNA dimer. Mutating the guanosine residues in these two motifs--only four nucleotides per genomic RNA--reduced packaging 100-fold, comparable to the level of nonspecific packaging. These results thus explain the selective packaging of dimeric RNA. This paradigm has implications for RNA recognition in general, illustrating how local context and RNA structure can create information-rich recognition signals from simple single-stranded sequence elements in large RNAs.     

Incurred sample reanalysis: enhancing the Bland-Altman approach with tolerance intervals

This article describes the need for incurred sample reanalysis and suggests that the combination of a Bland-Altman plot and tolerance intervals can provide a visual evaluation of method performance. It also shows how the proposed combination is a tool that may be of value in determining minimum sample size. An example dataset is worked through in its entirety so that a reader unfamiliar with the topic can gain sufficient information to analyze their own data. Related topics include the generation of 66.7% tolerance factors, comparison of mean-normalized and log differences and the use of probability plots to evaluate error distributions. The suggestions presented in this article are meant to be a continuation of the ongoing incurred sample reanalysis discussion and, as such, further comment is invited.     

Impact of life stage and duration of exposure on arsenic-induced proliferative lesions and neoplasia in C3H mice

Epidemiological studies suggest that chronic exposure to inorganic arsenic is associated with cancer of the skin, urinary bladder and lung as well as the kidney and liver. Previous experimental studies have demonstrated increased incidence of liver, lung, ovary, and uterine tumors in mice exposed to 85 ppm (∼8 mg/kg) inorganic arsenic during gestation. To further characterize age susceptibility to arsenic carcinogenesis we administered 85 ppm inorganic arsenic in drinking water to C3H mice during gestation, prior to pubescence and post-pubescence to compare proliferative lesion and tumor outcomes over a one-year exposure period. Inorganic arsenic significantly increased the incidence of hyperplasia in urinary bladder (48%) and oviduct (36%) in female mice exposed prior to pubescence (beginning on postnatal day 21 and extending through one year) compared to control mice (19 and 5%, respectively). Arsenic also increased the incidence of hyperplasia in urinary bladder (28%) of female mice continuously exposed to arsenic (beginning on gestation day 8 and extending though one year) compared to gestation only exposed mice (0%). In contrast, inorganic arsenic significantly decreased the incidence of tumors in liver (0%) and adrenal glands (0%) of male mice continuously exposed from gestation through one year, as compared to levels in control (30 and 65%, respectively) and gestation only (33 and 55%, respectively) exposed mice. Together, these results suggest that continuous inorganic arsenic exposure at 85 ppm from gestation through one year increases the incidence and severity of urogenital proliferative lesions in female mice and decreases the incidence of liver and adrenal tumors in male mice. The paradoxical nature of these effects may be related to altered lipid metabolism, the effective dose in each target organ, and/or the shorter one-year observational period.     

Association of psychiatric and substance use disorder comorbidity with cocaine dependence severity and treatment utilization in cocaine-dependent individuals

The relations among psychiatric and substance dependence disorders and treatment utilization are of interest both for their clinical management and for health services. We examined these relations using six self-reported indices of cocaine dependence severity and three self-reported measures of treatment utilization and self-help group participation for cocaine dependence. The sample consisted of dyads: namely, a cocaine-dependent adult proband (N=449) and a cocaine-dependent sibling (N=449). Psychiatric and substance use disorders were assessed with the Semi-structured Assessment for Drug Dependence and Alcoholism. We controlled for the nesting within families of proband-sibling dyads and for demographic features using generalized estimating equation linear and logistic regression analyses. We found that psychiatric disorders were associated with an increased likelihood of cocaine dependence treatment or self-help group participation, but with only one of six indices of cocaine dependence severity. Bipolar disorder and antisocial personality disorder were associated with greater past heavy cocaine use, and with utilizing self-help but not treatment. Major depressive disorder and posttraumatic stress disorder were associated with treatment utilization and overall services utilization, respectively. The presence of other substance use disorders (SUDs) was the strongest correlate of cocaine dependence severity. Results suggest that co-occurring substance dependence and psychiatric disorders warrant attention in cocaine dependence assessment, treatment, and self-help.     

Ranibizumab combined with low-dose sorafenib for exudative age-related macular degeneration

Angiogenesis is a common factor in the pathogenesis of cancer and in exudative age-related macular degeneration (AMD). Therefore, angiogenesis inhibition has been developed as a therapeutic strategy. We report 2 cases of recurrent exudative AMD in which oral sorafenib, a tyrosine kinase inhibitor approved for cancer, was added to intravitreal ranibizumab, an antibody to vascular endothelial growth factor. These 2 patients were followed up by determination of visual acuity, fluorescein angiography, fundoscopy, and optical coherence tomography. The visual acuity of 1 patient improved from 20/70 to 20/60 while he was receiving sorafenib therapy; that of the other did not. Marked improvement was noted in both patients on optical coherence tomography. Additionally, both patients appeared to receive some benefit when low-dose oral sorafenib was used as monotherapy after its initial addition to ranibizumab therapy. Randomized trials of adding sorafenib to standard therapy for patients with neovascular AMD should be considered.