Hammond Kirk

The study was designed to determine whether urocortin 2 ( Ucn2 ) gene transfer is as safe and effective as metformin in insulin-resistant mice. Four groups of insulin-resistant db/db mice and a nondiabetic group were studied: (1) metformin; (2) Ucn2 gene transfer; (3) metformin + Ucn2 gene transfer; (4) saline; and (5) nondiabetic mice. After completion of the 15-week protocol, glucose disposal was quantified, safety assessed, and gene expression documented. Ucn2 gene transfer was superior to metformin, providing reductions in fasting glucose and glycated hemoglobin and enhanced glucose tolerance...

OBJECTIVE: To synthesize evidence for the effectiveness of self-management interventions for chronic health conditions that have symptom overlap with traumatic brain injury (TBI) in order to extract recommendations for self-management intervention in persons with TBI. DESIGN: An umbrella review of existing systematic reviews and/or meta-analyses of randomized controlled trials or nonrandomized studies targeting self-management of chronic conditions and specific outcomes relevant to persons with TBI...

Adenylyl cyclase 6 (AC6) synthesizes second messenger cAMP in G protein-coupled receptor (GPCR) signaling. In cochlear hair cells, AC6 distribution relies on an adhesion GPCR, ADGRV1, which is associated with Usher syndrome (USH), a condition of combined hearing and vision loss. ADGRV1 is a component of the USH type 2 (USH2) protein complex in hair cells and photoreceptors. However, the role of AC6 in the inner ear and retina has not been explored. Here, we found that AC6 distribution in hair cells depends on the USH2 protein complex integrity...

We developed an on-slide decellularization approach to generate acellular extracellular matrix (ECM) myoscaffolds that can be repopulated with various cell types to interrogate cell-ECM interactions. Using this platform, we investigated whether fibrotic ECM scarring affected human skeletal muscle progenitor cell (SMPC) functions that are essential for myoregeneration. SMPCs exhibited robust adhesion, motility, and differentiation on healthy muscle-derived myoscaffolds. All SPMC interactions with fibrotic myoscaffolds from dystrophic muscle were severely blunted including reduced motility rate and migration...

Role of blood-based factors in development and progression of heart failure (HF) is poorly characterized. Blood contains factors released during pathophysiological states that may impact cellular function and provide mechanistic insights to HF management. We tested effects of blood from two distinct HF models on cardiac metabolism and identified possible cellular targets of the effects. Blood plasma was obtained from daunorubicin- and myocardial infarction-induced HF rabbits (Dauno-HF and MI-HF) and their controls (Dauno-Control and MI-Control)...

OBJECTIVE: To describe the rates and causes of rehospitalization over a 10-year period following a moderate-severe traumatic brain injury (TBI) utilizing the Healthcare Cost and Utilization Project (HCUP) diagnostic coding scheme. SETTING: TBI Model Systems centers. PARTICIPANTS: Individuals 16 years and older with a primary diagnosis of TBI. DESIGN: Prospective cohort study. MAIN MEASURES: Rehospitalization (and reason for rehospitalization) as reported by participants or their proxies during follow-up telephone interviews at 1, 2, 5, and 10 years postinjury...

BACKGROUND: We used transverse aortic constriction (TAC) in mice to test the hypothesis that urocortin 2 (Ucn2) gene transfer would increase left ventricular (LV) systolic and diastolic function in the pressure stressed LV. METHODS: Three groups were studied: 1) control mice (no TAC); 2) mice that received saline 6w after TAC; and 3) mice that received Ucn2 gene transfer 6w after TAC, using adeno-associated virus 8 encoding murine Ucn2 (AAV8.mUcn2; 2x1013 genome copies (gc)/kg, i...

Several studies have characterized comorbidities among individuals with traumatic brain injury (TBI); however, there are few validated TBI comorbidity indices. Widely used indices (e.g., Elixhauser Comorbidity Index [ECI]) were developed in other patient populations and anchor to mortality or healthcare utilization, not functioning, and notably exclude conditions known to co-occur with TBI. The objectives of this study were to develop and validate a functionally relevant TBI comorbidity index (Fx-TBI-CI) and to compare prognostication of the Fx-TBI-CI with the ECI ...

SARS-CoV-2 is responsible for the 2020 global COVID-19 pandemic. In patients with COVID-19, multiple cardiovascular (CV) manifestations have been reported. SARS coronavirus 2 infection can lead to inflammatory CV disease first via takeover of the angiotensin-converting enzyme-2 enzyme as a cell receptor as well as the macrophage activation syndrome in severe illness. We review the CV manifestations of COVID-19 and therapeutics under investigation. We discuss the potential long-term CV sequelae after recovery from COVID-19 and the gaps in knowledge including the pathophysiological links between acute cardiac injury, myocardial inflammation and chronic cardiomyopathy...

Background: The Patient Protection Affordable Care Act has expanded Medicaid eligibility in recent years. However, the provisions of the act have not translated to improved Medicaid payments for specialists such as orthopaedic surgeons. The number of health care practitioners who accept Medicaid is already decreasing, with low reimbursement rates being cited as the primary reason for the trend. Hypothesis: Private practice orthopaedic groups will see patients with Medicaid or Medicare at lower rates than academic orthopaedic practices, and business days until appointment availability will be higher for patients with Medicaid and Medicare than those with private insurance...

Danon disease (DD) is a rare X-linked autophagic vacuolar myopathy associated with multiorgan dysfunction, including the heart, skeletal muscle, and liver. There are no specific treatments, and most male patients die from advanced heart failure during the second or third decade of life. DD is caused by mutations in the lysosomal-associated membrane protein 2 ( LAMP2 ) gene, a key mediator of autophagy. LAMP2 has three isoforms: LAMP2A, LAMP2B, and LAMP2C. LAMP2B is the predominant isoform expressed in cardiomyocytes...

Type 1 diabetes affects 20 million patients worldwide. Insulin is the primary and commonly the sole therapy for type 1 diabetes. However, only a minority of patients attain the targeted glucose control and reduced adverse events. We tested urocortin 2 gene transfer as single-agent therapy for insulin deficiency using two mouse models. Urocortin 2 gene transfer reduced blood glucose for months after a single intravenous injection, through increased skeletal muscle insulin sensitivity, increased insulin release in response to glucose stimulation, and increased plasma insulin levels before and during euglycemic clamp...

INTRODUCTION: Urocortin 2 (Ucn2) is a 38-amino acid peptide of the corticotropin-releasing factor family. Intravenous (IV) delivery of an adeno-associated virus vector serotype 8 encoding Ucn2 (AAV8.Ucn2) increases insulin sensitivity and glucose disposal in mice with insulin resistance. OBJECTIVE: To determine the effects of Ucn2 on liver metabolome. METHODS: Six-week-old C57BL6 mice were divided into normal chow (CHOW)-fed and high fat diet (HFD)-fed groups...

Prevalence of left ventricular (LV) systolic and diastolic dysfunction increases with aging. We previously reported that urocortin 2 (Ucn2) gene transfer increases heart function in mice with heart failure with reduced ejection fraction. Here, we test the hypotheses that (1) Ucn2 gene transfer will increase LV function in aged mice and that (2) Ucn2 gene transfer given in early life will prevent age-related LV dysfunction. Nineteen-month-old (treatment study) and 3-month-old (prevention study) mice received Ucn2 gene transfer or saline...

Engelmann spruce ( Picea engelmannii ) is a conifer found primarily on the west coast of North America. Here, we present the complete chloroplast genome sequence of Picea engelmannii genotype Se404-851. This chloroplast sequence will benefit future conifer genomic research and contribute resources to further species conservation efforts.

PURPOSE: We previously reported that inhibitory G protein (Gi) exerts intrinsic receptor-independent inhibitory activity upon adenylyl cyclase (AC) that regulates contractile force in rat ventricle. The two major subtypes of AC in the heart are AC5 and AC6. The aim of this study was to determine if this intrinsic Gi inhibition regulating contractile force is AC subtype selective. METHODS: Wild-type (WT), AC5 knockout (AC5KO) and AC6 knockout (AC6KO) mice were injected with pertussis toxin (PTX) to inactivate Gi or saline (control)...

Here, we present the complete chloroplast genome sequence of white spruce ( Picea glauca , genotype WS77111), a coniferous tree widespread in the boreal forests of North America. This sequence contributes to genomic and phylogenetic analyses of the Picea genus that are part of ongoing research to understand their adaptation to environmental stress.

BACKGROUND: Diabetes mellitus is associated with increased risk of heart failure. We previously demonstrated in mice that a single injection of adeno-associated virus 8 encoding urocortin 2 (AAV8.UCn2) increases glucose disposal in models of insulin resistance and improves function of the failing heart. In the present study, we tested the hypothesis that UCn2 gene transfer would reduce diabetes-related left ventricular (LV) dysfunction. METHODS: 8-week-old C57BL6 male mice fed a Western diet (WD; 45% fat, 35% carbohydrate) for 40 weeks...

A fusion protein (C1C2) constructed by fusing the intracellular C1 and C2 segments of adenylyl cyclase type 6 (AC6) retains beneficial effects of AC6 expression, without increasing cAMP generation. The effects of cardiac-directed C1C2 expression in pressure-overload is unknown. LV pressure overload was induced by transverse aortic constriction (TAC) in C1C2 mice and in transgene negative (TG-) mice. Four weeks after TAC, LV systolic and diastolic function were measured, and Ca2+ handling was assessed. Four weeks after TAC, TG- animals showed reduced LV peak +dP/dt...

UCn2 and UCn3 peptides have recently been infused to treat patients with heart failure (HF) but are limited by their short half-lives. A 1-time intravenous injection of virus vectors encoding UCn2 or UCn3 provided sustained increases in plasma concentrations of the peptides. This was associated with increases in both systolic and diastolic left ventricular (LV) function, mediated by increased LV SERCA2a expression and Ca2+ handling. UCn2, but not UCn3, gene transfer reduced fasting glucose and increased glucose disposal...