Publications

One of the many obstacles to effective drug treatment is the efflux transporter P-glycoprotein (P-gp), which can restrict the plasma and intracellular concentrations of numerous xenobiotics. Variable drug response to P-gp substrates suggests that genetic differences in ABCB1 may affect P-gp transport. The current study examined how ABCB1 variants alter the P-gp-mediated transport of probe substrates in vitro. Nonsynonymous ABCB1 variants and haplotypes with an allele frequency >/=2% were transiently expressed in HEK293T cells, and the transport of calcein acetoxymethyl ester and 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY-FL)-paclitaxel was measured in the absence or presence of the P-gp inhibitor cyclosporin A. The A893S, A893T, and V1251I variants and the N21D/1236C>T/A893S/3435C>T haplotype altered intracellular accumulation compared with reference P-gp in a substrate-dependent manner. It is interesting that certain variants showed altered sensitivity to cyclosporin A inhibition that was also substrate-specific. These functional data demonstrate that nonsynonymous polymorphisms in ABCB1 may selectively alter P-gp transport and drug-drug interactions in a substrate- and inhibitor-dependent manner.

BACKGROUND

Atrial fibrillation (AF) may be due to an inherited trait, particularly in lone AF patients. A family history of AF in lone AF patients has not previously been compared with a family history of patients with AF and established risk factors (non-lone AF).

OBJECTIVE

The purpose of this study was to compare the frequency of having a first-degree relative with AF in lone and non-lone AF patients.

METHODS

We performed a case-control study of consecutive subjects presenting to a single electrophysiology laboratory. A convenience sample of subjects with no known arrhythmias was also enrolled.

RESULTS

Four hundred twenty-nine subjects were enrolled: 136 had AF (54 with lone AF), 84 had atrial flutter, 158 had other supraventricular arrhythmias, and 51 had no known arrhythmias. Significantly more subjects with AF reported a first-degree family history of AF compared with the remainder of the cohort (25% vs. 5%; P <.001). In multivariable analysis adjusting for potential confounders, AF patients had a 6-fold greater odds of having a family member with AF (95% confidence interval [CI] 2.93-12.7; P <.001). Lone AF patients had a first-degree family member with AF substantially more often than those with non-lone AF (41% vs. 14%; P <.001). After adjusting for potential confounders, lone AF patients remained significantly more likely than other AF patients to have a first-degree relative with AF (OR 7.2; 95% CI 2.1-24.7; P = .002).

CONCLUSION

Lone AF patients have a first-degree family member with AF substantially more often than other AF patients. This suggests that an inherited trait may be particularly important in this subgroup of patients.

BACKGROUND

In Africa, fever is often treated presumptively as malaria, resulting in misdiagnosis and the overuse of antimalarial drugs. Rapid diagnostic tests (RDTs) for malaria may allow improved fever management.

METHODS

We compared RDTs based on histidine-rich protein 2 (HRP2) and RDTs based on Plasmodium lactate dehydrogenase (pLDH) with expert microscopy and PCR-corrected microscopy for 7000 patients at sites of varying malaria transmission intensity across Uganda.

RESULTS

When all sites were considered, the sensitivity of the HRP2-based test was 97% when compared with microscopy and 98% when corrected by PCR; the sensitivity of the pLDH-based test was 88% when compared with microscopy and 77% when corrected by PCR. The specificity of the HRP2-based test was 71% when compared with microscopy and 88% when corrected by PCR; the specificity of the pLDH-based test was 92% when compared with microscopy and >98% when corrected by PCR. Based on Plasmodium falciparum PCR-corrected microscopy, the positive predictive value (PPV) of the HRP2-based test was high (93%) at all but the site with the lowest transmission rate; the pLDH-based test and expert microscopy offered excellent PPVs (98%) for all sites. The negative predictive value (NPV) of the HRP2-based test was consistently high (>97%); in contrast, the NPV for the pLDH-based test dropped significantly (from 98% to 66%) as transmission intensity increased, and the NPV for expert microscopy decreased significantly (99% to 54%) because of increasing failure to detect subpatent parasitemia.

CONCLUSIONS

Based on the high PPV and NPV, HRP2-based RDTs are likely to be the best diagnostic choice for areas with medium-to-high malaria transmission rates in Africa.