Introduction: Geriatric trauma patients (GTP) make up an increasing percentage of the overall trauma population. Due to frailty, GTP are at an increased risk of morbidity and readmission. Therefore, ...it is becoming increasingly important to prognosticate outcomes to assist with resource utilization. We hypothesized that the "Identification of Seniors at Risk" (ISAR) score may correlate with both clinical outcomes and resource utilization for geriatric trauma patients. Methods: Patients older than 65 years who were admitted to the trauma service were screened using an ISAR scoring algorithm. Outcomes, including 30-day mortality, all-cause morbidity, hospital length of stay (LOS), intensive care unit (ICU) LOS, functional independence measures (FIM) at discharge, and percent discharged to a facility, were analyzed. Both descriptive and data-appropriate parametric and non-parametric statistical approaches were utilized, with significance set at α = 0.05. Results: One thousand and two hundred seventeen GTP were included in this study. The average age was 81, median injury severity score was 9, and 99% had a blunt trauma mechanism. ISAR scores were generally associated with increasing 30-day mortality (0%, 1.9%, 2.4%, and 2.1% for ISAR 0, ISAR 1-2, ISAR 3-4, and ISAR 5-6, respectively), morbidity (2.6%, 7.6%, 14.7%, and 7.3% for respective categories), longer hospital (3.1, 4.6, 5.1, and 4.3 days, respectively) and ICU stays (0.37, 0.64, 0.81, and 0.67, respectively), lower FIM score at discharge (18.5, 17.1, 15.8, and 14.4, for respective categories), as well as increasing percentage of patients discharged to a facility (29.8%, 58.9%, 72.1%, and 78.8% for respective categories). Conclusions: This exploratory study provides important early insight into potential relationships between ISAR and geriatric trauma outcomes. ISAR screening is a quick and easy-to-use tool that may be useful in GTP triage, level-of-care determination, and disposition planning. Understanding populations at risk, especially those with more intricate discharge needs, is an important step in mitigating those risks and implementing appropriate care plans.
Oxidative stress is a known contributing factor in mitochondrial respiratory chain (RC) disease pathogenesis. Yet, no efficient means exists to objectively evaluate the comparative therapeutic ...efficacy or toxicity of different antioxidant compounds empirically used in human RC disease. We postulated that pre-clinical comparative analysis of diverse antioxidant drugs having suggested utility in primary RC disease using animal and cellular models of RC dysfunction may improve understanding of their integrated effects and physiologic mechanisms, and enable prioritization of lead antioxidant molecules to pursue in human clinical trials. Here, lifespan effects of N-acetylcysteine (NAC), vitamin E, vitamin C, coenzyme Q10 (CoQ10), mitochondrial-targeted CoQ10 (MS010), lipoate, and orotate were evaluated as the primary outcome in a well-established, short-lived C. elegans gas-1(fc21) animal model of RC complex I disease. Healthspan effects were interrogated to assess potential reversal of their globally disrupted in vivo mitochondrial physiology, transcriptome profiles, and intermediary metabolic flux. NAC or vitamin E fully rescued, and coenzyme Q, lipoic acid, orotic acid, and vitamin C partially rescued gas-1(fc21) lifespan toward that of wild-type N2 Bristol worms. MS010 and CoQ10 largely reversed biochemical pathway expression changes in gas-1(fc21) worms. While nearly all drugs normalized the upregulated expression of the “cellular antioxidant pathway”, they failed to rescue the mutant worms' increased in vivo mitochondrial oxidant burden. NAC and vitamin E therapeutic efficacy were validated in human fibroblast and/or zebrafish complex I disease models. Remarkably, rotenone-induced zebrafish brain death was preventable partially with NAC and fully with vitamin E. Overall, these pre-clinical model animal data demonstrate that several classical antioxidant drugs do yield significant benefit on viability and survival in primary mitochondrial disease, where their major therapeutic benefit appears to result from targeting global cellular, rather than intramitochondria-specific, oxidative stress. Clinical trials are needed to evaluate whether the two antioxidants, NAC and vitamin E, that show greatest efficacy in translational model animals significantly improve the survival, function, and feeling of human subjects with primary mitochondrial RC disease.
•NAC and vitamin E rescue short lifespan in gas-1(fc21) complex I mutant C. elegans.•Several antioxidants partially rescue lifespan but improve healthspan in gas-1(fc21) worms.•Vitamin E, and partially NAC, prevents brain death in complex I inhibited D. rerio.•NAC improves cell viability in fibroblasts from complex I ND5 disease human subject.•Cellular OXIDATIVE stress is a highly relevant treatment target in mitochondrial disease.
The discovery of vibegron, a potent and selective human β3-AR agonist for the treatment of overactive bladder (OAB), is described. An early-generation clinical β3-AR agonist MK-0634 (3) exhibited ...efficacy in humans for the treatment of OAB, but development was discontinued due to unacceptable structure-based toxicity in preclinical species. Optimization of a series of second-generation pyrrolidine-derived β3-AR agonists included reducing the risk for phospholipidosis, the risk of formation of disproportionate human metabolites, and the risk of formation of high levels of circulating metabolites in preclinical species. These efforts resulted in the discovery of vibegron, which possesses improved druglike properties and an overall superior preclinical profile compared to MK-0634. Structure–activity relationships leading to the discovery of vibegron and a summary of its preclinical profile are described.
Propionic acidemia (PA) is a classical inborn error of metabolism with high morbidity that results from the inability of the propionyl-CoA carboxylase (PCC) enzyme to convert propionyl-CoA to ...methylmalonyl-CoA. PA is inherited in an autosomal recessive fashion due to functional loss of both alleles of either
PCCA
or
PCCB
. These genes are highly conserved across evolutionarily diverse species and share extensive similarity with
pcca-1
and
pccb-1
in the nematode,
Caenorhabditis elegans
. Here, we report the global metabolic effects of deletion in a single PCC gene, either
pcca-1
or
pccb-1,
in
C. elegans
. Animal lifespan was significantly reduced relative to wild-type worms in both mutant strains, although to a greater degree in
pcca-1
. Mitochondrial oxidative phosphorylation (OXPHOS) capacity and efficiency as determined by direct polarography of isolated mitochondria were also significantly reduced in both mutant strains. While in vivo quantitation of mitochondrial physiology was normal in
pccb-1
mutants,
pcca-1
deletion mutants had significantly increased mitochondrial matrix oxidant burden as well as significantly decreased mitochondrial membrane potential and mitochondrial content. Whole worm steady-state free amino acid profiling by UPLC revealed reduced levels in both mutant strains of the glutathione precursor cysteine, possibly suggestive of increased oxidative stress. Intermediary metabolic flux analysis by GC/MS with 1,6-
13
C
2
-glucose further showed both PCC deletion strains had decreased accumulation of a distal tricarboxylic acid (TCA) cycle metabolic intermediate (+1 malate), isotopic enrichment in a proximal TCA cycle intermediate (+1 citrate), and increased +1 lactate accumulation. GC/MS analysis further revealed accumulation in the PCC mutants of a small amount of 3-hydroxypropionate, which appeared to be metabolized in
C. elegans
to oxalate through a unique metabolic pathway. Collectively, these detailed metabolic investigations in translational PA model animals with genetic-based PCC deficiency reveal their significantly dysregulated energy metabolism at multiple levels, including reduced mitochondrial OXPHOS capacity, increased oxidative stress, and inhibition of distal TCA cycle flux, culminating in reduced animal lifespan. These findings demonstrate that the pathophysiology of PA extends well beyond what has classically been understood as a single PCC enzyme deficiency with toxic precursor accumulation, and suggest that therapeutically targeting the globally disrupted energy metabolism may offer novel treatment opportunities for PA. Summary: Two
C. elegans
model animals of propionic acidemia with single-gene
pcca-1
or
pccb-1
deletions have reduced lifespan with significantly reduced mitochondrial energy metabolism and increased oxidative stress, reflecting the disease’s broader pathophysiology beyond a single enzyme deficiency with toxic precursor accumulation.
Mitochondrial respiratory chain (RC) diseases are highly morbid multi-systemic conditions for which few effective therapies exist. Given the essential role of sirtuin and PPAR signaling in mediating ...both mitochondrial physiology and the cellular response to metabolic stress in RC complex I (CI) disease, we postulated that drugs that alter these signaling pathways either directly (resveratrol for sirtuin, rosiglitazone for PPARγ, fenofibrate for PPARα), or indirectly by increasing NAD(+) availability (nicotinic acid), might offer effective treatment strategies for primary RC disease. Integrated effects of targeting these cellular signaling pathways on animal lifespan and multi-dimensional in vivo parameters were studied in gas-1(fc21) relative to wild-type (N2 Bristol) worms. Specifically, animal lifespan, transcriptome profiles, mitochondrial oxidant burden, mitochondrial membrane potential, mitochondrial content, amino acid profiles, stable isotope-based intermediary metabolic flux, and total nematode NADH and NAD(+) concentrations were compared. Shortened gas-1(fc21) mutant lifespan was rescued with either resveratrol or nicotinic acid, regardless of whether treatments were begun at the early larval stage or in young adulthood. Rosiglitazone administration beginning in young adult stage animals also rescued lifespan. All drug treatments reversed the most significant transcriptome alterations at the biochemical pathway level relative to untreated gas-1(fc21) animals. Interestingly, increased mitochondrial oxidant burden in gas-1(fc21) was reduced with nicotinic acid but exacerbated significantly by resveratrol and modestly by fenofibrate, with little change by rosiglitazone treatment. In contrast, the reduced mitochondrial membrane potential of mutant worms was further decreased by nicotinic acid but restored by either resveratrol, rosiglitazone, or fenofibrate. Using a novel HPLC assay, we discovered that gas-1(fc21) worms have significant deficiencies of NAD(+) and NADH. Whereas resveratrol restored concentrations of both metabolites, nicotinic acid only restored NADH. Characteristic branched chain amino acid elevations in gas-1(fc21) animals were normalized completely by nicotinic acid and largely by resveratrol, but not by either rosiglitazone or fenofibrate. We developed a visualization system to enable objective integration of these multi-faceted physiologic endpoints, an approach that will likely be useful to apply in future drug treatment studies in human patients with mitochondrial disease. Overall, these data demonstrate that direct or indirect pharmacologic restoration of altered sirtuin and PPAR signaling can yield significant health and longevity benefits, although by divergent bioenergetic mechanism(s), in a nematode model of mitochondrial RC complex I disease. Thus, these animal model studies introduce important, integrated insights that may ultimately yield rational treatment strategies for human RC disease.
Mitochondrial DNA (mtDNA) sequence variation can influence the penetrance of complex diseases and climatic adaptation. While studies in geographically defined human populations suggest that mtDNA ...mutations become fixed when they have conferred metabolic capabilities optimally suited for a specific environment, it has been challenging to definitively assign adaptive functions to specific mtDNA sequence variants in mammals. We investigated whether mtDNA genome variation functionally influences Caenorhabditis elegans wild isolates of distinct mtDNA lineages and geographic origins. We found that, relative to N2 (England) wild-type nematodes, CB4856 wild isolates from a warmer native climate (Hawaii) had a unique p.A12S amino acid substitution in the mtDNA-encoded COX1 core catalytic subunit of mitochondrial complex IV (CIV). Relative to N2, CB4856 worms grown at 20°C had significantly increased CIV enzyme activity, mitochondrial matrix oxidant burden, and sensitivity to oxidative stress but had significantly reduced lifespan and mitochondrial membrane potential. Interestingly, mitochondrial membrane potential was significantly increased in CB4856 grown at its native temperature of 25°C. A transmitochondrial cybrid worm strain, chpIR (M, CB4856>N2), was bred as homoplasmic for the CB4856 mtDNA genome in the N2 nuclear background. The cybrid strain also displayed significantly increased CIV activity, demonstrating that this difference results from the mtDNA-encoded p.A12S variant. However, chpIR (M, CB4856>N2) worms had significantly reduced median and maximal lifespan relative to CB4856, which may relate to their nuclear–mtDNA genome mismatch. Overall, these data suggest that C. elegans wild isolates of varying geographic origins may adapt to environmental challenges through mtDNA variation to modulate critical aspects of mitochondrial energy metabolism.
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•mtDNA is exclusively inherited through the hermaphrodite in C. elegans.•mtDNA in C. elegans from England and Hawaii differ by one non-synonymous cox1 variant.•CIV activity at 20°C was increased in Hawaiian relative to England wild isolates.•Cybrid worm strain analysis confirmed functional effects of the COX1 p.A12S variant.•mtDNA variation functionally alters nematode metabolism and environmental adaptation.
A series of conformationally restricted acetanilides were synthesized and evaluated as β3-adrenergic receptor agonists (β3-AR) for the treatment of overactive bladder (OAB). Optimization studies ...identified a five-membered ring as the preferred conformational lock of the acetanilide. Further optimization of both the aromatic and thiazole regions led to compounds such as 19 and 29, which have a good balance of potency and selectivity. These compounds have significantly reduced intrinsic clearance compared to our initial series of pyridylethanolamine β3-AR agonists and thus have improved unbound drug exposures. Both analogues demonstrated dose dependent β3-AR mediated responses in a rat bladder hyperactivity model.
We present the case of a 68-year-old man with a tibioperoneal trunk mycotic pseudoaneurysm, a rarity in the modern age of antibiotics. We describe the patient's hospitalizations and workups that ...ultimately led to this diagnosis and our management with open ligation without bypass. This case highlights the importance of combining a thorough history and physical examination with laboratory and imaging data while keeping in mind a broad differential diagnosis.
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The synthesis of a novel class of piperazine benzamide (reverse amides) targeting the human β3-adrenergic receptor for the treatment of overactive bladder (OAB) is described. The SAR ...studies directed towards maintaining well established β3 potency and selectivities while improving the overall pharmacokinetic profile in the reverse amide class will be evaluated. The results and consequences associated with functional activity at the norepinephrine transporter (NET) will also be discussed.
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