Enzymes of drug metabolism during delirium

BACKGROUND: Delirium is common in ill medical patients. Several drugs and polypharmacy are recognised risk factors, yet little is known about drug metabolism in people with delirium. OBJECTIVE: The aim of this study was to investigate the activities of plasma esterases (drug metabolising enzymes) in delirium. DESIGN: This was a prospective study of delirium present at time of hospital admission (community acquired) or developing later (hospital acquired) in patients admitted as a medical emergency and aged 75 years or over. METHODS: Following informed consent or assent cognitive screening was completed on all patients on admission and every 48 hours subsequently. Delirium was diagnosed by Confusion Assessment Method and DSM IV criteria. Blood samples were taken on admission and at onset of delirium if this was later. Four plasma esterase assays were performed spectrophotometrically: acetylcholinesterase, aspirin esterase, benzoylcholinesterase, butyrylcholinesterase. RESULTS: 283 patients (71% of eligible) were recruited, with mean age 82.4 years and 59% female. 27% had community acquired delirium, 10% developed hospital acquired delirium, 63% never developed delirium. On admission the mean activities of all four esterase assays were statistically significantly lower in delirious than non delirious patients. There were no significant differences on admission in any plasma esterase activity between patients with hospital and community acquired delirium. In-hospital mortality was associated with low plasma esterase activities on admission. CONCLUSION: Plasma esterase activities are suppressed during delirium. These data reinforce the need for extreme caution with drugs in this vulnerable population.     

Absence of an intracellular cobalamin-binding protein in cultured fibroblasts from patients with defective synthesis of 5'-deoxyadenosylcobalamin and methylcobalamin

Three distinct classes of human mutations (cbl A, cbl B, and cbl C) cause defective synthesis of cobalamin (Cbl; vitamin B₁₂) coenzymes. Cultured fibroblasts from that unique class (cbl C) deficient in the synthesis of both Cbl coenzymes, 5′-deoxyadenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), were used to explore the underlying defect. We compared the uptake of transcobalamin II(TC II)-bound cyano[⁵⁷Co]cobalamin (CN-Cbl) by cbl cells with that of other control and mutant cell lines. Although the cbl C cells initially took up CN-[⁵⁷Co]Cbl normally, they were unable to retain it. To characterize this “leak” further, cell extracts were prepared following incubation and chromatographed on Sephadex G-150. After incubations of 1-2 hr, most of the CN-[⁵⁷Co]Cbl accumulated by control cells was still bound to TC II; the remainder was free. Thereafter, an ever-increasing fraction of the labeled Cbl eluted with an intracellular cobalamin-binding protein (ICB); more than 80% of the total was so bound after 76 hr incubations. ICB had an apparent molecular weight similar to that of several Cbl “R” binders (about 120,000), but was distinguished from them by its failure to react with specific anti-“R”binder antiserum. Significantly, no ICB was detected in extracts of three different cbl C lines even aftr prolonged incubations, whereas its appearance in cbl A, cbl B, and mutase apoenzyme mutants was normal. We propose: that ICB is required for retention of cobalamins by cells; and that cbl C cells “leak” cobalamins and show defective synthesis of Cbl coenzymes because they lack this intracellular binder.     

Ethidium bromide-(dC-dG-dC-dG)2 complex in solution: intercalation and sequence specificity of drug binding at the tetranucleotide duplex level.

The binding of ethidium bromide (EtdBr) to the dC-dG-dC-dG self-complementary duplex has been monitored at the resolvable drug and nucleic acid protons and backbone phosphates at high nucleotide/drug (N/D) ratios by nuclear magnetic resonance (NMR) spectroscopy in aqueous solution. We observe averaged resonances (25 degrees-95 degrees) for the nucleic acid and drug nonexchangeable protons in the presence of excess tetranucleotide (N/D = 24), indicative of rapid exchange relative to the chemical shifts in the free and complexed states. Complex formation results in upfield shifts for the base protons at the terminal and internal base pairs and an increase in the transition midpoint for the duplex-to-strand conversion. We observe upfield chemical shift changes of 1.2 ppm at the Watson-Crick guanine N-1 proton(s) on complex formation (N/D = 24), with slow exchange between (dC-dG-dC-dG)2 and EtdBr-(dC-dG-dC-dG)2 relative to this chemical shift difference at-5 degrees. The EtdBr phenanthridine ring protons shift upfield by about 0.9 ppm (H-2, H-4, H-7, H-9) and greater than 0.5 ppm (H-1, H-10) on complex formation, with the chemical shifts versus temperature plots (25 degrees-95 degrees) monitoring the dissociation of the EtdBr-(dC-dG-dC-dG)2 structure. These upfield shifts at the exchangeable and nonexchangeable base protons and phenanthridine ring (but not side chain) protons demonstrate intercalation of the phenanthridine ring of EtdBr into the dC-dG-dC-dG duplex in solution. The intercalation model may be supported by the observation of downfield shifts (up to 1ppm) at the internucleotide phosphate(s) of the tetranucleotide duplex on addition of EtdBr at low temperatures. We observe stronger binding of EtdBr to the self-complementary dC-dG-dC-dG (2 dC-dG intercalation sites) and dC-dC-dG-dG (1 dC-dG site) duplexes compared to the dG-dG-dC-dC (no dC-dG sites) as monitored by UV absorbance changes at 480 nm. These studies extend to the tetranucleotide duplex level earlier observations that EtdBr exhibits a selectivity for formation of complexes to dinucleoside monophosphates with a pyrimidine (3'-5') purine sequence in the crystal and in solution. The experimental proton NMR upfield shifts at the phenanthridine protons on formation of the EtdBr-(dC-dG-dC-dG)2 complex compare favorably with calculated values (atomic diamagnetic anisotropy and ring current contributions) based on the overlap geometry for EtdBr intercalated into the pyrimidine (3'-5') purine dinucleoside monophosphate duplex in the crystal.     

Suppression of E-protein activity interferes with the development of BCR-ABL-mediated myeloproliferative disease

E-proteins are a class of helix-loop-helix (HLH) proteins, which play multiple roles throughout lymphoid development. The DNA binding activities of the E-proteins are regulated by a distinct class of antagonistic HLH proteins, named Id1-4. Here we demonstrate that Id2 deficient mice in a C57BL/6 genetic background exhibit increased cellularity in the granulocyte/myeloid progenitor compartment and show significantly higher numbers of maturing neutrophils. Within 6 months of age, Id2 deficient mice succumbed from overwhelming granulocytosis. The disease closely mimicked the distinctive features of human chronic myeloid leukemia: leukocytosis with maturing neutrophils, splenomegaly, hepatomegaly, and myeloid infiltration into peripheral tissues, including spleen, liver, and lungs. Strikingly, forced Id2 expression in murine bone marrow cells substantially delayed the onset of myeloproliferative disease (MPD). Collectively, these studies show that suppression of E-protein activity interferes with the development of BCR-ABL-mediated MPD.     

Renal Artery Embolism

Renal artery embolism was first described in 1940, but it is only recently becoming recognized as a clinically significant entity. Although relatively uncommon, it is clearly responsible for considerable morbidity in patients who experience it. The pathogenesis is typically related to cardiac thrombus formation with subsequent embolization, although other etiologies have been described. The authors present a case report followed by a review of the literature to highlight the clinical characteristics of this phenomena. Presentation, diagnostics, and treatment options will be reviewed with the aim of increasing awareness of renal artery embolism. As clinicians become more familiar with this condition, they will be more likely to consider it as a possible diagnosis in patients with a typical presentation. This will hopefully lead to improved care through prompt diagnosis and treatment, particularly as one treatment option may be time sensitive.     

The Building Blocks Collaborative: Advancing a Life Course Approach to Health Equity Through Multi-Sector Collaboration

Too many children are born into poverty, often living in disinvested communities without adequate opportunities to be healthy and thrive. Two complementary frameworks—health equity and life course—propose new approaches to these challenges. Health equity strategies seek to improve community conditions that influence health. The life course perspective focuses on key developmental periods that can shift a person’s trajectory over the life course, and highlights the importance of ensuring that children have supports in place that set them up for long-term success and health. Applying these frameworks, the Alameda County Public Health Department launched the Building Blocks Collaborative (BBC), a countywide multi-sector initiative to engage community partners in improving neighborhood conditions in low-income communities, with a focus on young children. A broad cross-section of stakeholders, called to action by the state of racial and economic inequities in children’s health, came together to launch the BBC and develop a Bill of Rights that highlights the diverse factors that contribute to children’s health. BBC partners then began working together to improve community conditions by learning and sharing ideas and strategies, and incubating new collaborative projects. Supportive health department leadership; dedicated staff; shared vision and ownership; a flexible partnership structure; and broad collective goals that build on partners’ strengths and priorities have been critical to the growth of the BBC. Next steps include institutionalizing BBC projects into existing infrastructure, ongoing partner engagement, and continued project innovation—to achieve a common vision that all babies have the best start in life.     

Attitudes and Beliefs Regarding Cardiovascular Risk Factors Among Bangladeshi Immigrants in the US

The US has increasingly growing Bangladeshi population, a South Asian sub-ethnic group with a high prevalence of cardiovascular disease (CVD). We conducted a qualitative study using individual in-depth interviews to explore attitudes towards and difficulties with modifying CVD related behaviors among a Bangladeshi cohort. We interviewed 55 patients before reaching data saturation. Bangladeshis discussed the meaning of health and heart disease in the context of how disease can potentially impact their ability to care for their family. Behavioral and psychological factors were discussed as the causes of CVD. Internal forces and external forces were brought up to explain difficulties addressing the causes of CVD. Bangladeshi individuals in our study were aware of CVD, but felt unable to address behavioral risk factors. They cite a combination of internal and external factors as barriers to lifestyle modification. Interventions to address these barriers must simultaneously addressing self-efficacy and work-life balance.