Calcium channel blockers, survival and ischaemic stroke in patients with dementia: a Swedish registry study.

BACKGROUND: The effect of calcium channel blockers (CCB) on mortality and ischaemic stroke risk in dementia patients is understudied. OBJECTIVES: To calculate the risk of death and ischaemic stroke in dementia patients treated with CCBs, considering individual agents and dose response. METHODS: Longitudinal cohort study with 18 906 hypertensive dementia patients from the Swedish Dementia Registry (SveDem), 2008-2014. Other Swedish national registries contributed information on comorbidities, dispensed medication and outcomes. Individual CCB agents and cumulative defined daily doses (cDDD) were considered. RESULTS: In patients with hypertension and dementia, nifedipine was associated with increased mortality risk (aHR 1.32; CI 1.01-1.73; P < 0.05) compared to non-CCB users. Patients diagnosed with Alzheimer's dementia (AD) or dementia with Lewy bodies/Parkinson's disease dementia (DLB-PDD) taking amlodipine had lower mortality risk (aHR, 0.89; CI, 0.80-0.98; P < 0.05 and aHR 0.58; CI, 0.38-0.86; P < 0.01, respectively), than those taking other CCBs. Amlodipine was associated with lower stroke risk in patients with Alzheimer's dementia compared to other CCBs (aHR 0.63; CI, 0.44-0.89; P < 0.05). Sensitivity analyses with propensity score-matched cohorts repeated the results for nifedipine (aHR 1.35; 95% CI, 1.02-1.78; P < 0.05) and amlodipine in AD (aHR, 0.87; CI, 0.78-0.97; P < 0.05) and DLB-PDD (aHR, 0.56, 95%CI, 0.37-0.85; P < 0.05). CONCLUSION: Amlodipine was associated with reduced mortality risk in dementia patients diagnosed with AD and DLB-PDD. AD patients using amlodipine had a lower risk of ischaemic stroke compared to other CCB users.

Retroviral nucleocapsid protein specifically recognizes the base and the ribose of mononucleotides and mononucleotide components.

The interaction of the retroviral nucleocapsid protein (NC) with nucleic acids forms the basis of its varied roles in the replication cycle, which include binding and condensing the viral RNA within the virion, stimulation of the early steps in reverse transcription, and dissociation from RNA in the replication complex. As part of an investigation of the NC binding site and of the forces that drive its interaction with nucleic acids, the relative affinities of NC from avian myeloblastosis virus were determined for a series of mononucleotides and mononucleotide components using a competitive displacement assay utilizing the extrinsic fluorescent probe bis-ANS [Secnik, J., Wang, Q., Chang, C.-M., & Jentoft, J.E. (1990) Biochemistry 29, 7991-7997]. The estimated binding affinities were unexpectedly similar for nucleotides, nucleosides, and bases (Ka greater than 10(6) M-1). AMP, UMP, GMP, and CMP bound to NC with essentially equal affinity, indicating that NC does not discriminate between bases. This is consistent with its role in coating, condensing, and packaging the RNA within virions. Nucleosides, bases, riboses, and ribose phosphate bind to NC with 1000-fold higher affinity than inorganic phosphate, indicating that the NC binding site includes elements that recognize nucleotide base and ribose components in addition to phosphate ions. However, the binding affinities of components are not additive, i.e., the Kapp values for adenine and deoxyribose are very similar to that for deoxyadenosine, indicating that the interaction between the NC subsite and the base and the sugar components is complex. The stoichiometry of the complex between bis-ANS and NC was established to be NC.(bis-ANS)3.(ABSTRACT TRUNCATED AT 250 WORDS)

Interactions at the nucleic acid binding site of the avian retroviral nucleocapsid protein: studies utilizing the fluorescent probe 4,4'-bis(phenylamino)(1,1'-binaphthalene)-5,5'-disulfonic acid.

The structural and functional properties of the nucleocapsid (NC) protein of the avian myeloblastosis virus were examined by steady-state fluorescence and fluorescence anisotropy measurements of the complex between the NC and the extrinsic fluorophore 4,4'-bis(phenylamino)(1,1'-binaphthalene)-5,5'-disulfonic acid (bis-ANS). The intrinsic fluorescence of bis-ANS is enhanced many fold upon forming a complex with the NC. Between 2 and 10 molecules of bis-ANS bind strongly to the NC, with an overall Kd of less than 10(-6) M. The emission of bis-ANS in the complex can also be induced by excitation at 298 nm, indicating that energy is transferred from Trp 80, the sole tryptophan in the NC protein, to bis-ANS. The energy transferred between the Trp 80 and bis-ANS was analyzed to yield a calculated distance of separation between these fluorophores of 28 +/- 3 A; thus, Trp 80 is well removed from the nearest bound bis-ANS. The fluorescence emission of bis-ANS in the NC.bis-ANS complex is efficiently quenched by added salts and by poly(A), suggesting that salt (presumably anions), nucleic acid, and bis-ANS bind to the same, positively charged region on the NC protein. A site size of six nucleotides was determined for nucleic acid binding to the NC protein, with an estimated Kd of less than 10(-6) M. Salt (anion) binding is strong, but nonspecific, with a Kapp of 4 mM, raising the possibility that anion binding to the NC protein might regulate the interaction of the NC with viral RNA inside the host cell.