Extended length of stay and related costs associated with dementia in acute care hospitals in Ireland.

OBJECTIVE: To estimate the additional impact of dementia on in-patient length of stay (LOS) and related costs in Irish acute hospitals. Both principal and secondary diagnosis effects are estimated and valued. METHODS: This is a cross-sectional study based on administrative data collected on all public hospital in-patient discharges in Ireland for people aged 65 years and older in 2019. Coarsened exact matching (CEM) was undertaken to account for observed confounders between dementia and non-dementia groups, while generalised linear modelling (GLM) was used to compare differences in LOS. RESULTS: Patients with a principal diagnosis of dementia spent on average 17.5 (CI: 15.42, 19.56; p < .01) d longer in hospital than similar patients with no principal diagnosis of dementia. LOS was 6.7 (CI: 6.31, 7.14; p < .01) d longer for patients with a secondary diagnosis of dementia compared to similar patients with no secondary diagnosis of dementia. The additional annual cost of care for patients in hospitals with a secondary (principal) diagnosis of dementia was €62.0 million (€13.2 million). CONCLUSIONS: This study highlights the economic impact of extended LOS for patients with dementia in Irish acute hospitals. Addressing specific dementia-related needs of people in hospital is likely to optimise resource use and decrease health care costs in acute care settings.

Admission to long-stay residential care and mortality among people with and without dementia living at home but on the boundary of residential care: a competing risks survival analysis.

BACKGROUND: Health policy in many countries is underpinned by a commitment to support dependent older people to remain in their own home for as long as possible and practicable. This study explores factors affecting both admission to long-stay residential care (LSRC) and mortality among people with and without dementia who are currently living at home with intensive formal care support. METHODS: This is a cross-sectional study based on administrative data collected on 429 dependent older people in Ireland, 269 of whom were people with dementia. A cause-specific hazard model was used to investigate the hazard of admission to LSRC, while accounting for mortality as a competing risk and vice versa. RESULTS: Admission to LSRC was higher for people with dementia relative to people without and for those receiving lower amounts of informal care. The hazard of mortality was significantly higher for older people aged 85+, whereas it was lower for individuals with a medium level of dependency relative to those with high levels of dependency. The hazard of mortality was also influenced by the amount of informal care provision. CONCLUSION: People with dementia are more likely to be admitted to LSRC than people without. Care for people with dementia needs to be more specialised and personal, and intensity of provision should not be equated to the number of care hours on offer. Informal care provision may help to prevent admission to LSRC. Advanced age, physical dependency and informal care provision affect mortality, raising interesting issues in relation to resource allocation.

A comparison of self and proxy quality of life ratings for people with dementia and their carers: a European prospective cohort study.

Objectives: To identify correlates of self-rated and proxy-rated quality of life (QoL) in people with dementia on (i) a dementia-specific and (ii) a capability-wellbeing QoL measure at baseline and 12-month follow-up, and to consider such factors in the context of QoL intervention development.Method: Prospective clinical and demographic data were collected from 451 community-dwelling dyads (mild-moderate dementia) across eight European countries. QoL was measured using the QOL-AD and the ICECAP-O. Multivariate modelling identified correlates of self- and proxy-rated QoL at baseline and at 12-month follow-up.Results: Carer's proxy-ratings of QoL were significantly lower than self-ratings at all time-points for both measures. Proxy-ratings declined over time, but self-ratings remained stable. Baseline predictors of greater self-rated QoL were education, and greater functional ability and relationship quality. Greater proxy-rated QoL was associated with education and greater functional ability, relationship quality, carer social support and carer QoL, lower carer anxiety/depression and less severe neuropsychiatric symptoms in people with dementia. At follow-up, greater self-rated QoL was predicted by greater functional ability, relationship quality, carer social support and having a spousal carer. Greater proxy-rated QoL at follow-up was associated with the same factors as at baseline; however, the dyad living together was an additional predictive factor.Conclusion: Both proxy-ratings and self-ratings of QoL should be interpreted with caution and in the context of each individual caregiving relationship. Different functional, psychosocial, relational and contextual factors influence self- and proxy-ratings, and both sets of factors should be considered in the context of QoL intervention development for the dyad.

A Study of the Patients Admitted to the Clinical Decision Unit over One Year.

Clinical decision units (CDUs) are areas within an emergency department (ED) providing care for the patient who may benefit from an extended observation period, usually for a maximum of twenty-four hours. A retrospective patient record audit was performed to determine the characteristics of patients admitted to the Cork University Hospital (CUH) CDU over 12 months. The average length of stay of a patient in the CDU was 29 hours. The most common diagnoses admitted to the CDU were chest pain (9.5%) and headache (7.2%). The research implies that the CDU provided a means for CUH to save approximately €2 million annually.

Insights into the pathophysiology of catch-up compared with non-catch-up growth in children born small for gestational age: an integrated analysis of metabolic and transcriptomic data.

Small for gestational age (SGA) children exhibiting catch-up (CU) growth have a greater risk of cardiometabolic diseases in later life compared with non-catch-up (NCU) SGA children. The aim of this study was to establish differences in metabolism and gene expression profiles between CU and NCU at age 4-9 years. CU children (n=22) had greater height, weight and body mass index standard deviation scores along with insulin-like growth factor-I (IGF-I) and fasting glucose levels but lower adiponectin values than NCU children (n=11; all P<0.05). Metabolic profiling demonstrated a fourfold decrease of urine myo-inositol in CU compared with NCU (P<0.05). There were 1558 genes differentially expressed in peripheral blood mononuclear cells between the groups (P<0.05). Integrated analysis of data identified myo-inositol related to gene clusters associated with an increase in insulin, growth factor and IGF-I signalling in CU children (P<0.05). Metabolic and transcriptomic profiles in CU SGA children showed changes that may relate to cardiometabolic risk.

The effects of dependence and function on costs of care for Alzheimer's disease and mild cognitive impairment in Ireland.

OBJECTIVE: To explore the incremental effects of patient dependence and function on costs of care for patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI) in Ireland. METHODS: Cost analysis based on reported resource use for a cross-section of 100 community-based people with AD and MCI. Formal care included general practice visits, hospitalizations, outpatient clinic consultations, accident and emergency visits, respite care, meals on wheels services and other health and social care professional consultations. Informal care included time input provided by caregivers. Resource unit costs were applied to value formal care and the opportunity cost method was used to value informal care. Patient dependence on others was measured using the Dependence Scale and patient functional capacity using the Disability Assessment for Dementia scale. Multivariate regression analysis was used to model the cost of care. RESULTS: Both dependence and function were independently and significantly associated with total formal and informal care cost: a one point increase in dependence was associated with a €796 increase in total cost and a one point improvement in function with a €417 reduction in total cost over 6 months. Patient function was significantly associated with formal care costs, whereas patient function and dependence were both significantly associated with informal care costs. CONCLUSION: The costs of care for patients with AD and MCI in Ireland are substantial. Interventions that reduce patient dependence on others and functional decline may be associated with important economic benefits.

Dopamine D(1) receptor deletion strongly reduces neurotoxic effects of methamphetamine.

Methamphetamine (METH) is a potent, highly addictive psychostimulant consumed worldwide. In humans and experimental animals, repeated exposure to this drug induces persistent neurodegenerative changes. Damage occurs primarily to dopaminergic neurons, accompanied by gliosis. The toxic effects of METH involve excessive dopamine (DA) release, thus DA receptors are highly likely to play a role in this process. To define the role of D(1) receptors in the neurotoxic effects of METH we used D(1) receptor knock-out mice (D(1)R(-/-)) and their WT littermates. Inactivation of D(1)R prevented METH-induced dopamine fibre loss and hyperthermia, and increases in gliosis and pro-inflammatory molecules such as iNOS in the striatum. In addition, D(1)R inactivation prevented METH-induced loss of dopaminergic neurons in the substantia nigra. To explore the relationship between hyperthermia and neurotoxicity, METH was given at high ambient temperature (29 °C). In this condition, D(1)R(-/-) mice developed hyperthermia following drug delivery and the neuroprotection provided by D(1)R inactivation at 23 °C was no longer observed. However, reserpine, which empties vesicular dopamine stores, blocked hyperthermia and strongly potentiated dopamine toxicity in D(1)R(-/-) mice, suggesting that the protection afforded by D(1)R inactivation is due to both hypothermia and higher stored vesicular dopamine. Moreover, electrical stimulation evoked higher DA overflow in D(1)R(-/-) mice as demonstrated by fast scan cyclic voltammetry despite their lower basal DA content, suggesting higher vesicular DA content in D(1)R(-/-) than in WT mice. Altogether, these results indicate that the D(1)R plays a significant role in METH-induced neurotoxicity by mediating drug-induced hyperthermia and increasing the releasable cytosolic DA pool.

Nuclear transport and transcription.

The compartmentalization of DNA in the nucleus of eukaryotic cells establishes a connection between the nuclear transport machinery and the transcriptional apparatus. General transcription factors, as well as specific transcriptional activators and repressors, such as p53 and NF-AT, need to be imported into the nucleus following their translation. In addition, nuclear transport plays a crucial role in regulating the activity of many transcription factors.

The ins and outs of cell-polarity decisions.

The guanine-nucleotide-exchange factor Cdc24 is a critical regulator of cell polarity. Far1 is a key player in Cdc24 regulation, controlling Cdc24 activity in budding yeast by regulating its subcellular localization in response to two very different signals - one external and one internal.

Increased kynurenine concentration attenuates serotonergic neurotoxicity induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats through activation of aryl hydrocarbon receptor.

3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative that has been shown to produce serotonergic damage in the brains of primates, including humans, and of rats. Tryptophan, the precursor of serotonin, is primarily degraded through the kynurenine (KYN) pathway, producing among others KYN, the main metabolite of this route. KYN has been reported as an endogenous agonist of the aryl hydrocarbon receptor (AhR), a transcription factor involved in several neurological functions. This study aims to determine the effect of MDMA on the KYN pathway and on AhR activity and to establish their role in the long-term serotonergic neurotoxicity induced by the drug in rats. Our results show that MDMA induces the activation of the KYN pathway, mediated by hepatic tryptophan 2,3-dioxygenase (TDO). MDMA also activated AhR as evidenced by increased AhR nuclear translocation and CYP1B1 mRNA expression. Autoradiographic quantification of serotonin transporters showed that both the TDO inhibitor 680C91 and the AhR antagonist CH-223191 potentiated the neurotoxicity induced by MDMA, while administration of exogenous l-kynurenine or of the AhR positive modulator 3,3'-diindolylmethane (DIM) partially prevented the serotonergic damage induced by the drug. The results demonstrate for the first time that MDMA increases KYN levels and AhR activity, and these changes appear to play a role in limiting the neurotoxicity induced by the drug. This work provides a better understanding of the physiological mechanisms that attenuate the brain damage induced by MDMA and identify modulation of the KYN pathway and of AhR as potential therapeutic strategies to limit the negative effects of MDMA.

Mechanism of metabolic control. Target of rapamycin signaling links nitrogen quality to the activity of the Rtg1 and Rtg3 transcription factors.

De novo biosynthesis of amino acids uses intermediates provided by the TCA cycle that must be replenished by anaplerotic reactions to maintain the respiratory competency of the cell. Genome-wide expression analyses in Saccharomyces cerevisiae reveal that many of the genes involved in these reactions are repressed in the presence of the preferred nitrogen sources glutamine or glutamate. Expression of these genes in media containing urea or ammonia as a sole nitrogen source requires the heterodimeric bZip transcription factors Rtg1 and Rtg3 and correlates with a redistribution of the Rtg1p/Rtg3 complex from a predominantly cytoplasmic to a predominantly nuclear location. Nuclear import of the complex requires the cytoplasmic protein Rtg2, a previously identified upstream regulator of Rtg1 and Rtg3, whereas export requires the importin-beta-family member Msn5. Remarkably, nuclear accumulation of Rtg1/Rtg3, as well as expression of their target genes, is induced by addition of rapamycin, a specific inhibitor of the target of rapamycin (TOR) kinases. We demonstrate further that Rtg3 is a phosphoprotein and that its phosphorylation state changes after rapamycin treatment. Taken together, these results demonstrate that target of rapamycin signaling regulates specific anaplerotic reactions by coupling nitrogen quality to the activity and subcellular localization of distinct transcription factors.

Roles of phosphorylation sites in regulating activity of the transcription factor Pho4.

Transcription factors are often phosphorylated at multiple sites. Here it is shown that multiple phosphorylation sites on the budding yeast transcription factor Pho4 play distinct and separable roles in regulating the factor's activity. Phosphorylation of Pho4 at two sites promotes the factor's nuclear export and phosphorylation at a third site inhibits its nuclear import. Phosphorylation of a fourth site blocks the interaction of Pho4 with the transcription factor Pho2. Multiple phosphorylation sites provide overlapping and partially redundant layers of regulation that function to efficiently control the activity of Pho4.

Phosphorylation of the transcription factor PHO4 by a cyclin-CDK complex, PHO80-PHO85.

Induction of the yeast gene PHO5 is mediated by the transcription factors PHO2 and PHO4. PHO5 transcription is not detectable in high phosphate; it is thought that the negative regulators PHO80 and PHO85 inactivate PHO2 and PHO4. Here it is reported that PHO80 has homology to yeast cyclins and interacts with PHO85, a p34cdc2/CDC28-related protein kinase. The PHO80-PHO85 complex phosphorylates PHO4; this phosphorylation is correlated with negative regulation of PHO5. These results demonstrate the existence of a cyclin-cdk complex that is used for a regulatory process other than cell-cycle control and identify a physiologically relevant substrate for this complex.

Phosphate-regulated inactivation of the kinase PHO80-PHO85 by the CDK inhibitor PHO81.

A complex consisting of the cyclin-dependent kinase (CDK) PHO85 and the cyclin PHO80 phosphorylates and is thought to inactivate the transcription factor PHO4 when yeast cells are grown in medium containing high concentrations of phosphate. The CDK inhibitor PHO81 inhibits the kinase activity of the PHO80-PHO85 complex when Saccharomyces cerevisiae cells are grown in medium depleted of phosphate. A region of PHO81 with similarity to the mammalian CDK inhibitor p16INK4 is sufficient for inhibition in vitro. These studies demonstrate that CDK inhibitors are used to regulate kinases involved in processes other than cell cycle control and suggest that the ankyrin repeat motif may be commonly used for interaction with cyclin-CDK complexes.

Evidence that the leucine zipper is a coiled coil.

Recently, a hypothetical structure called a leucine zipper was proposed that defines a new class of DNA binding proteins. The common feature of these proteins is a region spanning approximately 30 amino acids that contains a periodic repeat of leucines every seven residues. A peptide corresponding to the leucine zipper region of the yeast transcriptional activator GCN4 was synthesized and characterized. This peptide associates in the micromolar concentration range to form a very stable dimer of alpha helices with a parallel orientation. Although some features of the leucine zipper model are supported by our experimental data, the peptide has the characteristics of a coiled coil.

Regulation of PHO4 nuclear localization by the PHO80-PHO85 cyclin-CDK complex.

PHO4, a transcription factor required for induction of the PHO5 gene in response to phosphate starvation, is phosphorylated by the PHO80-PHO85 cyclin-CDK (cyclin-dependent kinase) complex when yeast are grown in phosphate-rich medium. PHO4 was shown to be concentrated in the nucleus when yeast were starved for phosphate and was predominantly cytoplasmic when yeast were grown in phosphate-rich medium. The sites of phosphorylation on PHO4 were identified, and phosphorylation was shown to be required for full repression of PHO5 transcription when yeast were grown in high phosphate. Thus, phosphorylation of PHO4 by PHO80-PHO85 turns off PHO5 transcription by regulating the nuclear localization of PHO4.

X-ray structure of the GCN4 leucine zipper, a two-stranded, parallel coiled coil.

The x-ray crystal structure of a peptide corresponding to the leucine zipper of the yeast transcriptional activator GCN4 has been determined at 1.8 angstrom resolution. The peptide forms a parallel, two-stranded coiled coil of alpha helices packed as in the "knobs-into-holes" model proposed by Crick in 1953. Contacts between the helices include ion pairs and an extensive hydrophobic interface that contains a distinctive hydrogen bond. The conserved leucines, like the residues in the alternate hydrophobic repeat, make side-to-side interactions (as in a handshake) in every other layer of the dimer interface. The crystal structure of the GCN4 leucine zipper suggests a key role for the leucine repeat, but also shows how other features of the coiled coil contribute to dimer formation.

Preferential heterodimer formation by isolated leucine zippers from fos and jun.

The products of the nuclear oncogenes fos and jun are known to form heterodimers that bind to DNA and modulate transcription. Both proteins contain a leucine zipper that is important for heterodimer formation. Peptides corresponding to these leucine zippers were synthesized. When mixed, these peptides preferentially form heterodimers over homodimers by at least 1000-fold. Both homodimers and the heterodimer are parallel alpha helices. The leucine zipper regions from Fos and Jun therefore correspond to autonomous helical dimerization sites that are likely to be short coiled coils, and these regions are sufficient to determine the specificity of interaction between Fos and Jun. The Fos leucine zipper forms a relatively unstable homodimer. Instability of homodimers provides a thermodynamic driving force for preferential heterodimer formation.

Sequence requirements for coiled-coils: analysis with lambda repressor-GCN4 leucine zipper fusions.

A genetic system was developed in Escherichia coli to study leucine zippers with the amino-terminal domain of bacteriophage lambda repressor as a reporter for dimerization. This system was used to analyze the importance of the amino acid side chains at eight positions that form the hydrophobic interface of the leucine zipper dimer from the yeast transcriptional activator, GCN4. When single amino acid substitutions were analyzed, most functional variants contained hydrophobic residues at the dimer interface, while most nonfunctional sequence variants contained strongly polar or helix-breaking residues. In multiple randomization experiments, however, many combinations of hydrophobic residues were found to be nonfunctional, and leucines in the heptad repeat were shown to have a special function in leucine zipper dimerization.