Medical Decision-Making Incapacity among Newly Diagnosed Older Patients with Hematological Malignancy Receiving First Line Chemotherapy: A Cross-Sectional Study of Patients and Physicians

Background

Decision-making capacity to provide informed consent regarding treatment is essential among cancer patients. The purpose of this study was to identify the frequency of decision-making incapacity among newly diagnosed older patients with hematological malignancy receiving first-line chemotherapy, to examine factors associated with incapacity and assess physicians’ perceptions of patients’ decision-making incapacity.

Methods

Consecutive patients aged 65 years or over with a primary diagnosis of malignant lymphoma or multiple myeloma were recruited. Decision-making capacity was assessed using the Structured Interview for Competency and Incompetency Assessment Testing and Ranking Inventory-Revised (SICIATRI-R). Cognitive impairment, depressive condition and other possible associated factors were also evaluated.

Results

Among 139 eligible patients registered for this study, 114 completed the survey. Of these, 28 (25%, 95% confidence interval [CI]: 17%-32%) were judged as having some extent of decision-making incompetency according to SICIATRI-R. Higher levels of cognitive impairment and increasing age were significantly associated with decision-making incapacity. Physicians experienced difficulty performing competency assessment (Cohen’s kappa -0.54).

Conclusions

Decision-making incapacity was found to be a common and under-recognized problem in older patients with cancer. Age and assessment of cognitive impairment may provide the opportunity to find patients that are at a high risk of showing decision-making incapacity.     

Soybean β-Conglycinin Prevents Age-Related Hearing Impairment

Obesity-related complications are associated with the development of age-related hearing impairment. β-Conglycinin (β-CG), one of the main storage proteins in soy, offers multiple health benefits, including anti-obesity and anti-atherosclerotic effects. Here, to elucidate the potential therapeutic application of β-CG, we investigated the effect of β-CG on age-related hearing impairment. Male wild-type mice (age 6 months) were randomly divided into β-CG-fed and control groups. Six months later, the body weight was significantly lower in β-CG-fed mice than in the controls. Consumption of β-CG rescued the hearing impairment observed in control mice. Cochlear blood flow also increased in β-CG-fed mice, as did the expression of eNOS in the stria vascularis (SV), which protects vasculature. β-CG consumption also ameliorated oxidative status as assessed by 4-HNE staining. In the SV, lipofuscin granules of marginal cells and vacuolar degeneration of microvascular pericytes were decreased in β-CG-fed mice, as shown by transmission electron microscopy. β-CG consumption prevented loss of spiral ganglion cells and reduced the frequencies of lipofuscin granules, nuclear invaginations, and myelin vacuolation. Our observations indicate that β-CG ameliorates age-related hearing impairment by preserving cochlear blood flow and suppressing oxidative stress.     

Developmental genetic profiles of glutamate receptor system,neuromodulator system,protector of normal tissue and mitochondria,and reelin in marmoset cortex: Potential molecular mechanisms of pruning phase of spines in primate synaptic formation process during the end of infancy and prepuberty (II)

This is the second report of a series paper, which reports molecular mechanisms underlying the occurrence of pruning spine phase after rapid spinogenesis phase in neonates and young infant in the primate brain. We performed microarray analysis between the peak of spine numbers [postnatal 3 months (M)] and spine pruning (postnatal 6 M) in prefrontal, inferior temporal, and primary visual cortices of the common marmoset (Callithrix jacchus). The pruning phase is not clearly defined in rodents but is in primates including the marmoset. The differentially expressed genes between 3 M and 6 M in all three cortical areas were selected by two-way analysis of variance. The list of selected genes was analyzed by canonical pathway analysis using “Ingenuity Pathway Analysis of complex omics data” (IPA; Ingenuity Systems, Qiagen, Hilden, Germany). In this report, we discuss these lists of genes for the glutamate receptor system, G-protein-coupled neuromodulator system, protector of normal tissue and mitochondria, and reelin. (1) Glutamate is a common neurotransmitter. Its receptors AMPA1, GRIK1, and their scaffold protein DLG4 decreased as spine numbers decreased. Instead, GRIN3 (NMDA receptor) increased, suggesting that strong NMDA excitatory currents may be required for a single neuron to receive sufficient net synaptic activity in order to compensate for the decrease in synapse. (2) Most of the G protein-coupled receptor genes (e.g., ADRA1D, HTR2A, HTR4, and DRD1) in the selected list were upregulated at 6 M. The downstream gene ROCK2 in these receptor systems plays a role of decreasing synapses, and ROCK2 decreased at 6 M. (3) Synaptic phagosytosis by microglia with complement and other cytokines could cause damage to normal tissue and mitochondria. SOD1, XIAP, CD46, and CD55, which play protective roles in normal tissue and mitochondria, showed higher expression at 6 M than at 3 M, suggesting that normal brain tissue is more protected at 6 M. (4) Reelin has an important role in cortical layer formation. In addition, RELN and three different pathways of reelin were expressed at 6 M, suggesting that new synapse formation decreased at that age. Moreover, if new synapses were formed, their positions were free and probably dependent on activity.     

Developmental expression profiles of axon guidance signaling and the immune system in the marmoset cortex: Potential molecular mechanisms of pruning of dendritic spines during primate synapse formation in late infancy and prepuberty (I)

The synapse number and the related dendritic spine number in the cerebral cortex of primates shows a rapid increase after birth. Depending on the brain region and species, the number of synapses reaches a peak before adulthood, and pruning takes place after this peak (overshoot-type synaptic formation). Human mental disorders, such as autism and schizophrenia, are hypothesized to be a result of either too weak or excessive pruning after the peak is reached. Thus, it is important to study the molecular mechanisms underlying overshoot-type synaptic formation, particularly the pruning phase.     

Role of lactose on the production of d-arabitol by Kluyveromyces lactis grown on lactose

There are remarkably few reports on d-arabitol production from lactose. Previous studies in our laboratory have shown that the osmophilic yeast Kluyveromyces lactis NBRC 1903 convert lactose to extracellular d-arabitol. The present study was undertaken to determine the participation of osmotic stress caused by lactose on d-arabitol production by K. lactis NBRC 1903 and to provide the information on the kinetics of d-arabitol production from lactose by K. lactis NBRC 1903. It was confirmed that d-arabitol production was triggered when an initial lactose concentration was above 278 mmol L⁻¹. d-Arabitol yield increased with an increase in initial lactose concentration. The highest d-arabitol concentration of 79.5 mmol L⁻¹ was achieved in the cultivation of K. lactis NBRC 1903 in a medium containing 555 mmol L⁻¹ lactose and 40 g L⁻¹ yeast extract. Lactose was found to play two important roles in d-arabitol production by K. lactis NBRC 1903 grown on lactose. First, lactose was assimilated as the substrate both for cell growth and d-arabitol production. Second, a high lactose concentration induced cellular response to high osmotic stress and up-regulated the flow from d-glucose-6-phosphate to d-arabitol. The arrest of cell growth triggered d-arabitol production.     

A yeast one-hybrid system to screen for methylated DNA-binding proteins

We had previously exploited a method for targeted DNA methylation in budding yeast to succeed in one-hybrid detection of methylation-dependent DNA–protein interactions. Based on this finding, we developed a yeast one-hybrid system to screen cDNA libraries for clones encoding methylated DNA-binding proteins. Concurrent use of two independent bait sequences in the same cell, or dual-bait system, effectively reduced false positive clones, which were derived from methylation-insensitive sequence-specific DNA-binding proteins. We applied the dual-bait system to screen cDNA libraries and demonstrated efficient isolation of clones for methylated DNA-binding proteins. This system would serve as a unique research tool for epigenetics.     

Wild type and <Emphasis Type="Italic">H43Y</Emphasis> variant of human <Emphasis Type="Italic">TRIM5α</Emphasis> show similar anti-human immunodeficiency virus type 1 activity both in vivo and in vitro

Polymorphisms in human genes have been shown to affect the rate of disease progression to acquired immune deficiency syndrome in human immunodeficiency virus type 1 (HIV-1)-infected individuals. Recently, tripartite motif 5α (TRIM5α) was identified as a factor that confers resistance to HIV-1 infection in Old World monkey cells. Subsequently, Sawyer et al. (Curr Biol 16:95–100, 2006) reported a single nucleotide polymorphism (H43Y) in the human TRIM5α gene and TRIM5α protein with 43Y was found to lose its ability to restrict HIV-1. In the present study, we reevaluated effects of this allele on in vitro anti-HIV-1 activity as well as on HIV-1 disease progression in European and Asian cohorts of HIV-1-infected individuals. Our epidemiological and molecular biological findings clearly indicate H43Y has a very minor effect on anti-HIV-1 activity of TRIM5α, suggesting that this allele is immaterial, at least in HIV-1-infected Europeans and Asians.     

A compact multi-channel apparatus for automated real-time monitoring of bioluminescence

We have developed a multi-channel apparatus for automated monitoring of bioluminescence in real time. We designed this apparatus to be compact (230 mm wide, 600 mm deep, and 227.5 mm high) so that it can be operated in a relatively small commercially-available incubator. The apparatus can process 20 samples at maximum in a single run, providing enough processibility in small-scale experiments. We verified the reliability and sensitivity of the apparatus by observing circadian bioluminescence rhythms over one week from a bioluminescent reporter strain (E9) of the cyanobacterium Synechococcus sp. strain PCC 7942 [Ishiura, M., Kutsuna, S., Aoki, S., Iwasaki, H., Andersson, C.R., Tanabe, A., Golden, S.S., Johnson, C.H., Kondo, T., Expression of a gene cluster kaiABC as a circadian feedback process in cyanobacteria, Science, 281 (1998) 1519-1523]. Our apparatus allows flexible experimental designs and will be effectively used for the studies of gene expression in various purposes.     

Activation of histidine decarboxylase through post-translational cleavage by caspase-9 in a mouse mastocytoma P-815

L-Histidine decarboxylase (HDC) is the rate-limiting enzyme for histamine synthesis in mammals. Although accumulating evidence has indicated the post-translational processing of HDC, it remains unknown what kinds of proteases are involved. We investigated the processing of HDC in a mouse mastocytoma, P-815, using a lentiviral expression system. HDC was expressed as a 74-kDa precursor form, which is cleaved to yield the 55- and 60-kDa forms upon treatment with butyrate. Alanine-scanning mutations revealed that two tandem aspartate residues (Asp(517)-Asp(518), Asp(550)-Asp(551)) are critical for the processing. Treatment with butyrate caused an increase in the enzyme activity of the cells expressing the wild type HDC, but not in the cells expressing the processing-incompetent mutant. An increase in histamine synthesis by butyrate was accompanied by formation of the 55- and 60-kDa form of HDC. In addition, the in vitro translated 74-kDa form of HDC was found to undergo a limited cleavage by purified human caspase-9, whereas the alanine-substituted mutants were not. Processing and enzymatic activation of HDC in P-815 cells was enhanced in the presence of a Zn(2+) chelator, TPEN. Although treatment with butyrate and TPEN drastically augmented the protease activity of caspase-3, and -9, no apoptotic cell death was observed. Both enzymatic activation and processing of HDC were completely suppressed by a pan-caspase inhibitor, partially but significantly by a specific inhibitor for caspase-9, but not by a caspase-3 inhibitor. These results suggest that, in P-815 cells, histamine synthesis is augmented through the post-translational cleavage of HDC, which is mediated by caspase-9.