Colorectal Cancer in Elderly Patients with Surgical Indication: State of the Art, Current Management, Role of Frailty and Benefits of a Geriatric Liaison

Six out of every 10 new colorectal cancer (CRC) diagnoses are in people over 65 years of age. Current standardized surgical approaches have proved to be tolerable on the elderly population, although post-operative complications are more frequent than in the younger CRC population. Frailty is common in elderly CRC patients with surgical indication, and it appears to be also associated with an increase of post-operative complications. Fast-track pathways have been developed to assure and adequate post-operative recovery, but comprehensive geriatric assessments (CGA) are still rare among the preoperative evaluation of elderly CRC patients. This review provides a thorough study of the effects that a CGA assessment and a geriatric intervention have in the prognosis of CRC elderly patients with surgical indication

Análisis molecular, electrofisiológico y comportamental de los efectos del péptido beta-amiloide en el hipocampo de roedores

La enfermedad de Alzheimer (EA) es una enfermedad neurodegenerativa, crónica y progresiva de la cual se estima que en 2050 habrá cerca de 115.4 millones de casos. Debido al grado de envejecimiento de la población, y dado que es una demencia incapacitante, representa un problema epidemiológico a escala mundial. Una de las hipótesis que intenta explicar la fisiopatología de la EA es la presencia del péptido beta-amiloide, Aß, en áreas concretas del sistema nervioso central como el hipocampo. Actualmente no existe consenso en cuanto a cómo el Aß altera la fisiología de neuronas, sinapsis, redes y sistemas del cerebro, ni de cómo se genera el estado de disfunción. En esta línea, se postula que la alteración de la actividad de sistemas de neurotransmisión excitatoria e inhibitoria promueve estados de hiperexcitabilidad de poblaciones y redes neuronales afectando a la actividad sincrónica de éstas, dando lugar a la aparición de déficits cognitivos de memoria asociados a la EA. Los modelos experimentales han ayudado a identificar varias moléculas y dianas implicadas en el proceso patogénico de la enfermedad. En particular, recientemente se han identificado dos canales de potasio (K+) que controlan la excitabilidad neuronal, los canales de potasio rectificadores de corriente de entrada acoplados a proteína G, GirK, y los canales de K+ dependientes de voltaje, KCNQ. El trabajo presentado en esta tesis doctoral se ha centrado en el estudio de los efectos de Aß25-35 en el hipocampo. Este es el primer estudio en el cual se aportan evidencias a nivel molecular, electrofisiológico y comportamental sobre los posibles mecanismos por los cuales Aß podría generar un estado de disfunción sináptica a través de los canales GirK. Los canales GirK son canales de K+ regulados por la unión de proteínas G, implicados en el control de la excitabilidad neuronal por regulación del potencial de membrana en reposo y generación de corrientes postsinápticas inhibitorias. Aß a través de distintos mecanismos y/o cascadas de señalización intracelular, modularía la actividad de los canales GirK afectando a la excitabilidad de los circuitos del hipocampo y la integración de la información sináptica. Estas alteraciones prolongadas en el tiempo podrían generar un desbalance entre los sistemas excitatorios e inhibitorios, dando lugar al estado de disfunción sináptica que puede estar desencadenando los déficits de memoria característicos de las etapas tempranas de la EA

Amyloid-β(25-35) Modulates the Expression of GirK and KCNQ Channel Genes in the Hippocampus.

During early stages of Alzheimer's disease (AD), synaptic dysfunction induced by toxic amyloid-β (Aβ) is present before the accumulation of histopathological hallmarks of the disease. This scenario produces impaired functioning of neuronal networks, altered patterns of synchronous activity and severe functional deficits mainly due to hyperexcitability of hippocampal networks. The molecular mechanisms underlying these alterations remain unclear but functional evidence, shown by our laboratory and others, points to the involvement of receptors/channels which modulate neuronal excitability, playing a pivotal role in early Aβ-induced AD pathogenesis. In particular, two potassium channels that control neuronal excitability, G protein-coupled activated inwardly-rectifying potassium channel (GirK), and voltage-gated K channel (KCNQ), have been recently linked to Aβ pathophysiology in the hippocampus. Specifically, by using Aβ25-35, we previously found that GirK conductance is greatly decreased in the hippocampus, and similar effects have also been reported on KCNQ conductance. Thus, in the present study, our goal was to determine the effect of Aβ on the transcriptional expression pattern of 17 genes encoding neurotransmitter receptors and associated channels which maintain excitatory-inhibitory neurotransmission balance in hippocampal circuits, with special focus in potassium channels. For this purpose, we designed a systematic and reliable procedure to analyze mRNA expression by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) in hippocampal rat slices incubated with Aβ25-35. We found that: 1) Aβ down-regulated mRNA expression of ionotropic GluN1 and metabotropic mGlu1 glutamate receptor subunits as previously reported in other AD models; 2) Aβ also reduced gene expression levels of GirK2, 3, and 4 subunits, and KCNQ2 and 3 subunits, but did not change expression levels of its associated GABAB and M1 receptors, respectively. Our results provide evidence that Aβ can modulate the expression of these channels which could affect the hippocampal activity balance underlying learning and memory processes impaired in AD

RNA integrity and quality.

<p>RNA quality indicator (RQI) for hippocampal slices and percentage of samples for each RQI value range.</p

Experimental design, RNA integrity category examples and reference gene selection.

<p><b>(A)</b> Horizontal hippocampal brain slices from one hemisphere were obtained using a dissecting microscope. Thick dashed lines indicate the cutting delimitation area. C, Caudal; L, Lateral. <b>(B)</b> Schematic representation of hippocampal slices incubation procedure. Slices were incubated in ACSF or A<i>β</i> 1°μM during 30 or 120 min. At time zero, hippocampal slices were considered as raw tissue and mRNA level for these samples 100% since incubation effects had no begun. All experiments were performed at room temperature and bubbled with carbogen gas. <b>(C)</b> Representative examples of electropherogram of different RNA samples revealing RNA integrity levels and virtual images of the gels for each sample. Left column (M), molecular weight marker; Right column (S), RNA sample. RQI values are ranged from 10 (intact) to 1 (totally degraded). The gradual degradation of RNA extracted from hippocampal slices was reflected by a continuous shift towards shorter fragment sizes. The first peak found in all traces corresponds to a molecular weight marker. Electropherogram plots from top to bottom: (Top) Profile of RNA with RQI = 9.1. The peaks correspond to 18S and 28S ribosomal subunits. In this case, there are no small peaks in profile which would indicate RNA degradation. Two bands corresponding to the 28S and 18S ribosomal RNA respectively. The greater thickness of the band corresponding to 28S indicates higher concentration compared to 18S subunit. (Middle) Profile of RNA with RQI = 7.1. Arrows indicate the different peaks from degraded RNA fragments which appear at different time points along the reaction. In the sample are arrowed degraded fragments of different sizes. (Bottom) RNA profile with RQI = 2.1. Plot corresponding to highly degraded RNA can be observed. No bands can be distinguished. <b>(D)</b> The BestKeeper and NormFinder softwares were used to calculate the most stable gene among the 3 reference genes, in ACSF and A<i>β</i> incubation. For both softwares the most stable gene is that with the lowest stability value. Asterisk indicates the selected gene (Ppia) as the most stably expressed reference gene. <i>Actb</i>, β-actin; <i>Gapdh</i>, Glyceraldehyde 3-phosphate dehydrogenase, <i>Ppia</i>, Peptidylprolyl isomerase A.</p

Relative expression of the main receptor and channel genes involved in excitatory and inhibitory hippocampal neurotransmission systems during A<i>β</i> incubation.

<p>Expression levels of mRNA for <b>(A)</b> glutamatergic <b>(B</b>) cholinergic and <b>(C)</b> GABAergic genes, at 0, 30 and 120 min after ACSF (control) or A<i>β</i> incubation, were analyzed by qPCR and normalized to <i>Ppia</i>, the most stably expressed reference gene in our study. Normalized 2^–ΔCq expression for each gene and time point is presented as percentage of gene expression at time 0 (t = 0 min) which is considered as 100% basal control expression. <b>(A)</b>. Relative mRNA expression levels of glutamatergic NMDA receptor subunits <i>GluN1</i>, <i>GluN2A</i> and <i>GluN2B</i>, AMPA receptor subunits <i>GluA1</i> and <i>GluA2</i>, and metabotropic receptor <i>mGlu1</i> and <i>mGlu5</i>. <b>(B)</b> Relative mRNA expression levels of GABA_B receptor subunits <i>GABA</i>_<i>B1</i> and <i>GABA</i>_<i>B2</i>, and GABA_B receptor effector GIRK channel subunits <i>Girk1</i>, <i>Girk2</i>, <i>Girk3</i> and <i>Girk4</i>. <b>(C)</b> Relative mRNA expression levels of cholinergic M1 receptor and M1 receptor effector KCNQ channel subunits <i>Kcnq2</i>, <i>Kcnq3</i> and <i>Kcnq5</i>. <b>(D)</b> Relative mRNA expression levels of activity-regulated cytoskeleton-associated protein, <i>Arc</i>, at 0, 30 and 120 min after ACSF or A<i>β</i> incubation are also shown. Note that y-scale in D is different to A-C. Data are presented as mean ± standard error of the mean (SEM). *<i>p</i> < 0.05. A<i>β</i>, amyloid-beta; <i>Ppia</i>, Peptidylprolyl isomerase A; <i>ACSF</i>, artificial cerebrospinal fluid.</p

Effects of exercise interventions on the functional status of acutely hospitalised older adults: a systematic review and meta-analysis

Background Acute hospitalisation can have adverse effects in older adults, notably functional decline. We aimed to summarize evidence on the effects of exercise interventions in acutely hospitalised older adults. Methods Relevant articles were systematically searched (PubMed, Web of Science, Rehabilitation & Sports Medicine Source, and EMBASE) until 19th March 2020. Randomized controlled trials (RCTs) of in-hospital exercise interventions versus usual care conducted in older adults (>60yrs) hospitalised for an acute medical condition were included. Methodological quality of the studies was assessed with the PEDro scale. Primary outcomes included functional independence and physical performance. Intervention effects were also assessed for other major outcomes (length of hospital stay, incidence of readmission, and mortality). A meta-analysis was conducted when ≥3 studies analysed the same outcome. Results Fifteen studies from 12 RCTs (n = 1748) were included. Methodological quality of the studies was overall high. None of the studies reported any adverse event related to the intervention. Exercise interventions improved functional independence at discharge (standardized mean difference [SMD] = 0.64, 95% confidence interval = 0.19–1.08) and 1–3 months post-discharge (SMD = 0.29, 95%CI = 0.13–0.43), as well as physical performance (SMD = 0.57, 95%CI = 0.18–0.95). No between-group differences were found for length of hospital stay or risk of readmission or mortality (all p > 0.05). Conclusions In-hospital supervised exercise interventions seem overall safe and effective for improving – or attenuating the decline of – functional independence and physical performance in acutely hospitalised older adults. The clinical relevance of these findings remains to be confirmed in future research.Sin financiación10.895 JCR (2020) Q1, 25/195 Cell Biology3.523 SJR (2020) Q1, 1/35 AgingNo data IDR 2019UE

Impairments of Synaptic Plasticity Induction Threshold and Network Oscillatory Activity in the Hippocampus Underlie Memory Deficits in a Non-Transgenic Mouse Model of Amyloidosis

In early Alzheimer disease (AD) models synaptic failures and upstreaming aberrant patterns of network synchronous activity result in hippocampal-dependent memory deficits. In such initial stage, soluble forms of Amyloid-&beta; (A&beta;) peptides have been shown to play a causal role. Among different A&beta; species, A&beta;25&ndash;35 has been identified as the biologically active fragment, as induces major neuropathological signs related to early AD stages. Consequently, it has been extensively used to acutely explore the pathophysiological events related with neuronal dysfunction induced by soluble A&beta; forms. However, the synaptic mechanisms underlying its toxic effects on hippocampal-dependent memory remain unresolved. Here, in an in vivo model of amyloidosis generated by intracerebroventricular injections of A&beta;25&ndash;35 we studied the synaptic dysfunction mechanisms underlying hippocampal cognitive deficits. At the synaptic level, long-term potentiation (LTP) of synaptic excitation and inhibition was induced in CA1 region by high frequency simulation (HFS) applied to Schaffer collaterals. A&beta;25&ndash;35 was found to alter metaplastic mechanisms of plasticity, facilitating long-term depression (LTD) of both types of LTP. In addition, aberrant synchronization of hippocampal network activity was found while at the behavioral level, deficits in hippocampal-dependent habituation and recognition memories emerged. Together, our results provide a substrate for synaptic disruption mechanism underlying hippocampal cognitive deficits present in A&beta;25&ndash;35 amyloidosis model

Effect of a Simple Exercise Program on Hospitalization-Associated Disability in Older Patients: A Randomized Controlled Trial

Objective Hospitalization-associated disability [HAD, ie, the loss of ability to perform ≥1 basic activities of daily living (ADLs) independently at discharge] is a frequent condition among older patients. The present study assessed whether a simple inpatient exercise program decreases HAD incidence in acutely hospitalized very old patients. Design In this randomized controlled trial (Activity in Geriatric Acute Care) participants were assigned to a control or intervention group and were assessed at baseline, admission, discharge, and 3 months thereafter. Setting and Participants In total, 268 patients (mean age 88 years, range 75–102) admitted to an acute care for older patients unit of a public hospital were randomized to a control (n = 125) or intervention (exercise) group (n = 143). Methods Both groups received usual care, and patients in the intervention group also performed simple supervised exercises (walking and rising from a chair, for a total duration of ∼20 minutes/day). We measured ADL function (Katz index) and incident HAD at discharge and after 3 months (primary outcome) and Short Physical Performance Battery, ambulatory capacity, number of falls, rehospitalization, and death during a 3-month follow-up (secondary outcomes). Results Median duration of hospitalization was 7 days (interquartile range 4 days). The intervention group had a lower risk of HAD with reference to both baseline [odds ratio (OR) 0.36; 95% confidence interval (CI) 0.17–0.76, P = .007] and admission (OR 0.29; 95% CI 0.10–0.89, P = .030). A trend toward an improved ADL function at discharge vs admission was found in the intervention group compared with controls (OR 0.32; 95% CI ‒0.04 to 0.68; P = .083). No between-group differences were noted for the other endpoints (all P > .05).Sin financiación4.669 JCR (2020) Q2, 15/53 Geriatrics & Gerontology1.840 SJR (2020) Q1, 9/108 Geriatrics and GerontologyNo data IDR 2019UE

Individual Responsiveness to Physical Exercise Intervention in Acutely Hospitalized Older Adults

We analyzed inter-individual variability in response to exercise among acutely hospitalized oldest-old adults. In this ancillary analysis of a randomized controlled trial, 268 patients (mean age 88 years) were assigned to a control (n = 125, usual care) or intervention group (n = 143, supervised exercise, i.e., walking and rising from a chair [1–3 sessions/day]). Intervention group patients were categorized as responders, non-responders, or adverse responders (improved, no change, or impaired function in activities of daily living [ADL, Katz index] from hospital admission to discharge, respectively). We analyzed the association between responsiveness to exercise and variables assessed at baseline (2 weeks pre-admission), admission, during hospitalization, at discharge, and during a subsequent 3-month follow-up. An impaired ADL function and worse nutritional status at admission were associated to a greater responsiveness, whereas a better ADL function at admission, longer hospitalization and lower comorbidity index were associated with a poorer response (p < 0.05). Adverse responders had worse outcomes at discharge and during the follow-up (e.g., impaired physical performance and greater fall number) (p < 0.05). Although exercise intervention helps to prevent ADL function decline in hospitalized oldest-old people, a number of them—particularly those with a better functional/health status at admission and longer hospitalization—are at higher risk of being adverse responders, which can have negative short/middle-term consequences.Sin financiación4.241 JCR (2020) Q1, 39/169 Medicine, General & InternalNo data SJR 2020No data IDR 2019UE