Background: Dementia leads to progressive cognitive and functional decline. Population aging is a concern, and the healthcare system must refocus its limited resources to keep up with service ...demands. Three cholinesterase inhibitors (ChEIs) – donepezil, galantamine and rivastigmine – have been approved for the treatment of dementia and are covered under Ontario’s formulary plan, but there has been little research regarding their economic impact. Methods: The purpose of this study was to describe the patterns of use of ChEIs, and to assess associated health resource utilization and costs to Ontario’s healthcare system. Anonymized patient-level data from seven provincial administrative databases were linked at the Institute for Clinical and Evaluative Sciences at Queen’s University. First-time users of ChEIs aged 66 years and older were identified between April 1 st, 2004 and March 31st, 2009, and were followed until treatment discontinuation or up to one year following their index date. Health resource use was classified into six care categories: prescription drugs, physicians, long-term care, home care nursing, emergency department, and hospitalizations. Chi-square, Kruskal-Wallis ANOVA and linear regression were employed to compare resource use between users of the three ChEIs. Results: In the cohort (N=40,057), the majority were prescribed donepezil (n=24,347), were female (60.5%) and had at least one other co-morbid disease. The odds of discontinuation were 1.47 (1.36, 1.60) and 1.26 (1.17, 136), higher for rivastigmine users than galantamine and donepezil users, respectively. Between 2005 and 2008, overall healthcare costs increased from $95.2 million to $106.1 million. Prescription drugs comprised 33% of all healthcare costs. ChEIs accounted for half of all prescription drug costs. Overall mean annual healthcare system cost per patient was $12,679.47 ($12,510.86, $12,848.08). Predictors of overall healthcare costs included long-term care, co-morbidity status, hospitalization and hip fractures. Conclusions: Prescription drugs account for a substantial proportion of healthcare costs for patients with dementia, and the amount attributable to ChEIs alone is significant. Knowing the health service utilization patterns for dementia patients can help healthcare professionals and decision-makers plan patient care and timely resource allocation. The results stress the utility of administrative databases and the need for further research for this disease.
A detailed kinetic analysis demonstrates that, in vitro, mutations in the PRM promoter of bacteriophage lambda can increase the rate of open complex formation at the divergent, lytic promoter PR in ...either of two ways. (1) PRM- mutations, typified by PRMKM11, indirectly stimulate PR by eliminating interference from RNA polymerase (RNAP) molecules bound at wild-type PRM. This effect can be observed only when PR is itself mutated because open complexes normally form so rapidly at wild-type PR that they are unaffected by PRM. It has been shown previously that PR and PRM can be occupied simultaneously by RNAP, suggesting that interference from PRM is mediated at a step subsequent to binding of RNAP to PR. This conclusion is supported by kinetic data, which indicate that inactivating PRM affects PRx3 by increasing kf, the rate of isomerization of closed to open complexes, four- to fivefold. (2) In addition to its indirect effect, the mutation PRM116, which is located at -33 with respect to PRM and -50 with respect to PR, directly increases the intrinsic strength of PR. PRM116 increases from 11 to 12 the number of A:T or T:A base-pairs in a 12 bp AT-rich sequence located between 47 and 58 bp upstream from PR; we suggest that this upstream sequence contributes directly to PR promoter strength. We also show that the PRx3 mutation causes a 100-fold decrease in kf. This result indicates that the -35 consensus region plays a major role in the isomerization of closed to open complexes at PR.
The medial temporal lobe (MTL) plays a critical role in transforming complex stimuli into permanent memory traces, yet little is known on how the activity of neurons in the human brain mediates this ...process. Recording from single neurons in the human MTL during visual encoding and retrieval of faces and objects, we found that in the hippocampus faces evoked predominantly suppression of neuronal firing below prestimulus baseline (‘inhibitory responses’). These responses were also prevalent in the entorhinal cortex but were absent in the amygdala during the first second of stimulus encoding when all responses to faces were ‘excitatory’ (neuronal firing increased above the prestimulus baseline). Inhibitory responses were more prevalent during recognition than encoding and were also present during processing of objects, albeit less frequently than during processing of faces. Despite the prevalence in the hippocampus of cells with inhibitory responses and their relative specificity to faces, it was mainly the activity of the cells with excitatory responses that was selective for stimulus features such as gender and emotional expression of faces. These findings suggest that a large population of cells with inhibitory responses is engaged in the hippocampal memory network, but primarily cells with excitatory responses process feature-specific information.
Thermal decomposition of the iron−manganese methoxycarbyne Cp(CO)Fe(μ-CO)(μ-COCH3)Mn(CO)MeCp (1a) occurs to give MeCpMn(CO)3 and in low yield CpFe(CO)2CH3; in the presence of PPh3, CpFe(CO)(PPh3)CH3 ...(2a) forms in high yield. The reaction is first-order in carbyne, but a side reaction that is also first-order in phosphine occurs to give Cp(CO)Fe(μ-CO)2Mn(CO)MeCp-CH3PPh3+ (3a) as a byproduct. Crossover experiments between 1a and its bis-MeCp, CD3 analogue 1b-d 3 result in scrambling of the methoxycarbyne methyl label between the products 2a and the MeCp analogue 2b. No alkyl exchange is seen in recovered starting materials in the reaction between 1a and bis-MeCp analogue 3b or (except after prolonged reaction) between the products 2a and 2b-d 3. “Control crossover” experiments between 1a and 2b-d 3 give complete alkyl scrambling. The data prove that alkyl exchange occurs among products after carbyne decomposition and presumably is induced by an intermediate that is formed by carbyne decomposition. Previous results show that the 16-electron intermediate CpFe(CO)CH3 forms at essentially the same rate from 2a as from 1a, ruling it out as the exchange intermediate since 2a and 2b-d 3 undergo only very slow exchange. A speculative proposal for the reactive intermediate is that it is the isomeric terminal methoxycarbyne CpFe⋮COCH3, and alkyl migration from oxygen to iron occurs after cluster cleavage. A detailed kinetic scheme for alkyl scrambling is proposed and tested by computer modeling: using an iterative procedure that couples numerical integration of the proposed rate equations with a simplex minimization algorithm designed to find the best rate constants, concentration data from several runs could be quantitatively fit to the proposed mechanism.
We have deleted a single base-pair in the -35 region of the bacteriophage lambda PRM promoter. The deletion (PRM delta 34) creates a better match of PRM to consensus, thereby substantially increasing ...the activity of the promoter in vitro and in vivo. Since the mutation also increases the overlap between OR2 and the -35 region of PRM, binding of repressor to OR2 no longer activates, but in fact represses PRM. Finally, the mutation decreases the distance between the PRM and PR transcription start sites from 82 to 81 base-pairs. As a consequence, the interaction of RNA polymerase with either promoter in vitro strongly inhibits open complex formation at the other. Kinetic analyses and DNase I protection assays lead to the surprising result that mutual inhibition is not due to steric occlusion. Both promoters can be occupied by RNA polymerase at the same time. Determination of KB and kf revealed that inhibition of PRM delta 34 by PR was manifest in a 100-fold decrease in the value of kf, but at the same time KB was increased tenfold. These data raise the possibility that RNA polymerase molecules bound at the two promoters contact and mutually stabilize each other and that this interaction subsequently inhibits a substep in the isomerization of closed to open complexes. In footprinting assays, each promoter is characterized by sites of enhanced cleavage when that promoter is occupied alone. These enhancements are substantially diminished when both promoters are occupied, suggesting that complexes of each promoter with RNA polymerase alter the structure of complexes formed at the other promoter. Assays of the effects of the delta 34 mutation in vivo indicate that interference between PRM and PR does not limit the rate of open complex formation at PRM in the cell. Apparently, transcription initiation clears the promoter rapidly enough that neither promoter is occupied a significant fraction of the time.
Carbapenem-resistant
(CRE) can be mechanistically classified into carbapenemase-producing
(CPE) and non-carbapenemase-producing carbapenem nonsusceptible
(NCPCRE). We sought to investigate the effect ...of antecedent carbapenem exposure as a risk factor for NCPCRE versus CPE. Among all patients with CRE colonization and infection, we conducted a case-control study comparing patients with NCPCRE (cases) and patients with CPE (controls). The presence of carbapenemases was investigated with phenotypic tests followed by PCR for predominant carbapenemase genes. We included 843 unique patients with first-episode CRE, including 387 (45.9%) NCPCRE and 456 (54.1%) CPE. The resistance genes detected in CPEs were
(42.8%),
(38.4%), and
(12.1%). After adjusting for confounders and clustering at the institutional level, the odds of prior 30-day carbapenem exposure was three times higher among NCPCRE than CPE patients (adjusted odds ratio aOR, 3.48; 95% confidence interval CI, 2.39 to 5.09;
< 0.001). The odds of prior carbapenem exposure and NCPCRE detection persisted in stratified analyses by
species (
and
) and carbapenemase gene (
and
). CPE was associated with male gender (aOR, 1.45; 95% CI, 1.07 to 1.97;
= 0.02), intensive care unit stay (aOR, 1.84; 95% CI, 1.24 to 2.74;
= 0.003), and hospitalization in the preceding 1 year (aOR, 1.42; 95% CI, 1.01 to 2.02;
= 0.05). In a large nationwide study, antecedent carbapenem exposure was a significant risk factor for NCPCRE versus CPE, suggesting a differential effect of antibiotic selection pressure.
Introduction. Intravenous high-dose vitamin C therapy is widely used in naturopathic and integrative oncology; however, a study reviewing its effects has never been performed in Singapore. This ...article serves to document administration of supportive vitamin C therapy for cancer patients in Singapore. Methods. The clinical response of 9 cancer patients of differing stages to the regular administration of large doses (25-100 g/d) of intravenous vitamin C (IVC; ascorbic acid) is outlined. Tumor pathology and patient health were verified by doctors who do not practice vitamin C treatment. Results. Cases suggesting survival beyond prognosis, improvement in quality of life, safe coadministration with and improved tolerance of conventional therapy, and deterioration in clinical condition following withdrawal of vitamin C therapy are documented clinically. Some patients experience the Jarisch-Herxheimer reaction—the release of endotoxin from microorganism death resulting in pimples, fever, and body odor—for a few hours after the therapy, but these are resolved quickly with no lasting effects. Conclusion. Randomized trials of IVC therapy are recommended because it has minimal side effects and has shown promising results.
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