Publications by authors named "Kelly Hamilton"

Article Synopsis
  • - This study investigates the prevalence and characteristics of frailty among outpatients with chronic kidney disease (CKD) and those on haemodialysis (HD), noting its significant impact on survival rates.
  • - In a cohort of 256 adult participants, 36.3% were frail, and 46.5% were prefrail, with frailty being a stronger predictor of mortality than age or comorbidities, showing a hazard ratio of 2.83.
  • - The findings suggest that frailty is common among CKD and HD patients, and while many showed stable frailty status, some exhibited improvement, highlighting that targeted interventions may enhance patient outcomes.
View Article and Find Full Text PDF

Background: Understanding the patient perspective of frailty is critical to offering holistic patient-centred care. Rehabilitation strategies for patients with advanced chronic kidney disease (CKD) and frailty are limited in their ability to overcome patient-perceived barriers to participation, resulting in high rates of drop-out and non-adherence. The aim of this study was to explore patient perspectives and preferences regarding experiences with rehabilitation to inform a CKD/Frailty rehabilitation model.

View Article and Find Full Text PDF

Problem-based learning (PBL) utilizes a self-directed strategy. This process relies on group participation to succeed. Students without a background in biology or medicine can feel overwhelmed by the complexity of the subject matter and unable to participate in the group learning process.

View Article and Find Full Text PDF

Up to 70 million people around the world suffer from rheumatoid arthritis. Current treatment options have varied efficacy and can cause unwanted side effects. New approaches are needed to treat this condition.

View Article and Find Full Text PDF

COVID-19 was declared an international public health emergency in January, and a pandemic in March of 2020. There are over 125 million confirmed COVID-19 cases that have caused over 2.7 million deaths worldwide as of March 2021.

View Article and Find Full Text PDF

Purpose: Oral cancer causes over 120,000 deaths annually and affects the quality of life for survivors. Over 90% of oral cancers are derived from oral squamous cell carcinoma cells (OSCCs) which are generally resistant to standard cytotoxic chemotherapy agents. OSCC cells often exhibit increased TGFβ and PDPN receptor activity compared to nontransformed oral epithelial cells.

View Article and Find Full Text PDF

COVID-19 was declared an international public health emergency in January, and a pandemic in March of 2020. There are over 23 million confirmed COVID-19 cases that have cause over 800 thousand deaths worldwide as of August 19th, 2020. COVID-19 is caused by the SARS-CoV-2 virus.

View Article and Find Full Text PDF

Traumatic brain injury often leads to progressive alterations at the molecular to circuit levels resulting in epilepsy and memory impairments. and models have provided a powerful platform for investigating the multimodal alteration after trauma. Recent analyses using voltage sensitive dye imaging, optogenetics, and glutamate uncaging have revealed circuit abnormalities following brain injury.

View Article and Find Full Text PDF

We introduce a theoretical framework of lesbian disclosure of sexual orientation in workplace contexts. Existing empirical research suggests (1) that disclosing one's sexual orientation results in positive, negative, and neutral workplace outcomes; and (2) that scholarship focused specifically on lesbian disclosure in workplace contexts is relatively limited. We extend this literature by introducing new theory that suggests that reactions to disclosure of lesbian identities will vary as a function of self-presentation.

View Article and Find Full Text PDF

Bhlhe40 is a transcription factor that is highly expressed in the hippocampus; however, its role in neuronal function is not well understood. Here, we used Bhlhe40 null mice on a congenic C57Bl6/J background (Bhlhe40 KO) to investigate the impact of Bhlhe40 on neuronal excitability and synaptic plasticity in the hippocampus. Bhlhe40 KO CA1 neurons had increased miniature excitatory post-synaptic current amplitude and decreased inhibitory post-synaptic current amplitude, indicating CA1 neuronal hyperexcitability.

View Article and Find Full Text PDF

Neural circuits in mammalian brains consist of large numbers of different cell types having different functional properties. To better understand the separate roles of individual neuron types in specific aspects of spatial learning and memory, we perturbed the function of principal neurons in vivo during maze performance or in hippocampal slices during recording of evoked excitatory synaptic potentials. Transgenic mice expressing the Drosophila allatostatin receptor (AlstR) in cortical and hippocampal pyramidal cells were tested on an elevated plus maze, in a Y-maze, and in the Morris water maze.

View Article and Find Full Text PDF

Memory consolidation benefits from post-training sleep. However, recent studies suggest that sleep does not uniformly benefit all memory, but instead prioritizes information that is important to the individual. Here, we examined the effect of test expectation on memory consolidation across sleep and wakefulness.

View Article and Find Full Text PDF

Numerous studies demonstrate that post-training sleep benefits human memory. At the same time, emerging data suggest that other resting states may similarly facilitate consolidation. In order to identify the conditions under which non-sleep resting states benefit memory, we conducted an EEG (electroencephalographic) study of verbal memory retention across 15min of eyes-closed rest.

View Article and Find Full Text PDF

Purpose: To develop a tool based on siRNA-mediated knockdown of hepatic P450 oxidoreductase (POR) to decrease the CYP-mediated metabolism of small molecule drugs that suffer from rapid metabolism in vivo, with the aim of improving plasma exposure of these drugs.

Methods: siRNA against the POR gene was delivered using lipid nanoparticles (LNPs) into rats. The time course of POR mRNA knockdown, POR protein knockdown, and loss of POR enzyme activity was monitored.

View Article and Find Full Text PDF

The importance of neuronal morphology has been recognized from the early days of neuroscience. Elucidating the functional roles of axonal and dendritic arbors in synaptic integration, signal transmission, network connectivity, and circuit dynamics requires quantitative analyses of digital three-dimensional reconstructions. We extensively searched the scientific literature for all original reports describing reconstructions of neuronal morphology since the advent of this technique three decades ago.

View Article and Find Full Text PDF

Pyridyl aminothiazoles comprise a novel class of ATP-competitive Chk1 inhibitors with excellent inhibitory potential. Modification of the core with ethylenediamine amides provides compounds with low picomolar potency and very high residence times. Investigation of binding parameters of such compounds using X-ray crystallography and molecular dynamics simulations revealed multiple hydrogen bonds to the enzyme backbone as well as stabilization of the conserved water molecules network in the hydrophobic binding region.

View Article and Find Full Text PDF

Translation of significant biochemical activity of pyridyl aminothiazole class of Chk1 inhibitors into functional CEA potency required analysis and adjustment of both physical properties and kinase selectivity profile of the series. The steps toward optimization of cellular potency included elimination of CDK7 activity, reduction of molecular weight and polar surface area and increase in lipophilicity of the molecules in the series.

View Article and Find Full Text PDF

Moderate release of the major stress hormones, glucocorticoids (GCs), improves hippocampal function and memory. In contrast, excessive or prolonged elevations produce impairments. Enzymatic degradation and reformation of GCs help to maintain optimal levels within target tissues, including the brain.

View Article and Find Full Text PDF

A number of inhibitors of kinesin spindle protein (KSP) have been described, which are known from X-ray crystallography studies to bind to an induced fit pocket defined by the L5 loop. We describe the characterization of eight mutant forms of KSP in which six residues that line this pocket have been altered. Mutants were analyzed by measuring rates of enzyme catalysis, in the presence and absence of six KSP inhibitors of four diverse structural classes and of varied ATP-competition status.

View Article and Find Full Text PDF

A high throughput screening campaign was designed to identify allosteric inhibitors of Chk1 kinase by testing compounds at high concentration. Activity was then observed at K(m) for ATP and at near-physiological concentrations of ATP. This strategy led to the discovery of a non-ATP competitive thioquinazolinone series which was optimized for potency and stability.

View Article and Find Full Text PDF

Inhibition of kinesin spindle protein (KSP) is a novel mechanism for treatment of cancer with the potential to overcome limitations associated with currently employed cytotoxic agents. Herein, we describe a C2-hydroxymethyl dihydropyrrole KSP inhibitor ( 11) that circumvents hERG channel binding and poor in vivo potency, issues that limited earlier compounds from our program. However, introduction of the C2-hydroxymethyl group caused 11 to be a substrate for cellular efflux by P-glycoprotein (Pgp).

View Article and Find Full Text PDF

The kinesin spindle protein (KSP, also known as Eg5) is essential for the proper separation of spindle poles during mitosis, and inhibition results in mitotic arrest and the formation of characteristic monoaster spindles. Several distinct classes of KSP inhibitors have been described previously in the public and patent literature. However, most appear to share a common induced-fit allosteric binding site, suggesting a common mechanism of inhibition.

View Article and Find Full Text PDF

From HTS lead 1, a novel benzoisoquinolinone class of ATP-competitive Chk1 inhibitors was devised and synthesized via a photochemical route. Using X-ray crystallography as a guide, potency was rapidly enhanced through the installation of a tethered basic amine designed to interact with an acidic residue (Glu91) in the enzyme pocket. Further SAR was explored at the solvent front and near to the H1 pocket and resulted in the discovery of low MW, sub-nanomolar inhibitors of Chk1.

View Article and Find Full Text PDF

Observations from two structurally related series of KSP inhibitors led to the proposal and discovery of dihydropyrazolobenzoxazines that possess ideal properties for cancer drug development. The synthesis and characterization of this class of inhibitors along with relevant pharmacokinetic and in vivo data are presented. The synthesis is highlighted by a key [3+2] cycloaddition to form the pyrazolobenzoxazine core followed by diastereospecific installation of a quaternary center.

View Article and Find Full Text PDF

The development of 2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-ones as inhibitors of Chk1 kinase is described. Introduction of a fused ring at the C7/C8 positions of the pyrazoloquinolinone provided an increase in potency while guidance from overlapping inhibitor bound Chk1 X-ray crystal structures contributed to the discovery of a potent and solubilizing propyl amine moiety in compound 52 (Chk1 IC(50)=3.1 nM).

View Article and Find Full Text PDF

A PHP Error was encountered

Severity: Warning

Message: fopen(/var/lib/php/sessions/ci_sessioni09t88o4mu9pdjf6b8jh5hvqfa22j6pv): Failed to open stream: No space left on device

Filename: drivers/Session_files_driver.php

Line Number: 177

Backtrace:

File: /var/www/html/index.php
Line: 316
Function: require_once

A PHP Error was encountered

Severity: Warning

Message: session_start(): Failed to read session data: user (path: /var/lib/php/sessions)

Filename: Session/Session.php

Line Number: 137

Backtrace:

File: /var/www/html/index.php
Line: 316
Function: require_once