The evidence that frequency modulated (FM) 50 kHz ultrasonic vocalizations (USVs) reflect a positive emotional state in rats is reviewed. Positive emotional states in humans are measured by ...facial-vocal displays (e.g., Duchenne smiling and laughter), approach behavior, and subjective self-report of feeling states. In laboratory animals, only facial-vocal displays, along with approach behavior can be measured. FM 50 kHz USVs are uniquely elevated by hedonic stimuli and suppressed by aversive stimuli. Rates of FM 50 kHz USVs are positively correlated to the rewarding value of the eliciting stimulus. Additionally, playbacks of these vocalizations are rewarding. The neural and pharmacological substrates of 50 kHz USVs are consistent with those of human positive affective states. By experimentally eliciting FM 50 kHz USVs, the novel molecular underpinning of positive affect can be elucidated and may be similar to those in humans. In humans, positive emotional states confer resilience to depression and anxiety, as well as promote overall health. Using rough-and-tumble play induced hedonic USVs, we have identified insulin like growth factor I and the NR2B subunit of the NMDA receptor as playing a functional role in positive affective states. From this research, we have developed a promising new class of antidepressants that is entering phase II clinical trials for the treatment of depression.
Abstract Total hip arthroplasty (THA) may produce blood loss requiring allogenic blood transfusion. Recently several authors have reported success decreasing their transfusion rate with tranexamic ...acid (TXA). We retrospectively reviewed our last 1595 primary THA in 1494 patients looking at whether the patients received TXA via IV infusion, topical application, or neither, and the need for a blood transfusion. Infusion of TXA acid produced a statistically significant difference in transfusion rate (p < 0.001) while topical TXA failed to reach statistical significance ( P = 0.15). The transfusion rate without TXA was 19.86%, 4.39% with TXA infusion (odds ratio = 5.36), and 12.86% (odds ratio = 1.67) with topical TXA.
The N-methyl-d-aspartate receptor-ionophore complex plays a key role in learning and memory and has efficacy in animals and humans with affective disorders. GLYX-13 is an N-methyl-d-aspartate ...receptor (NMDAR) glycine-site functional partial agonist and cognitive enhancer that also shows rapid antidepressant activity without psychotomimetic side effects.
The authors review the mechanism of action of GLYX-13 that was investigated in preclinical studies and evaluated in clinical studies. Specifically, the authors review its pharmacology, pharmacokinetics, and drug safety that were demonstrated in clinical studies.
NMDAR full antagonists can produce rapid antidepressant effects in treatment-resistant subjects; however, they are often accompanied by psychotomimetic effects that make chronic use outside of a clinical trial inpatient setting problematic. GLYX-13 appears to exert its antidepressant effects in the frontal cortex via NMDAR-triggered synaptic plasticity. Understanding the mechanistic underpinning of GLYX-13's antidepressant action should provide both novel insights into the role of the glutamatergic system in depression and identify new targets for therapeutic development.
Recent human clinical studies with the NMDA receptor (NMDAR) antagonist ketamine have revealed profound and long-lasting antidepressant effects with rapid onset in several clinical trials, but ...antidepressant effects were preceded by dissociative side effects. Here we show that GLYX-13, a novel NMDAR glycine-site functional partial agonist, produces an antidepressant-like effect in the Porsolt, novelty induced hypophagia, and learned helplessness tests in rats without exhibiting substance abuse-related, gating, and sedative side effects of ketamine in the drug discrimination, conditioned place preference, pre-pulse inhibition and open-field tests. Like ketamine, the GLYX-13-induced antidepressant-like effects required AMPA/kainate receptor activation, as evidenced by the ability of NBQX to abolish the antidepressant-like effect. Both GLYX-13 and ketamine persistently (24 h) enhanced the induction of long-term potentiation of synaptic transmission and the magnitude of NMDAR-NR2B conductance at rat Schaffer collateral-CA1 synapses in vitro. Cell surface biotinylation studies showed that both GLYX-13 and ketamine led to increases in both NR2B and GluR1 protein levels, as measured by Western analysis, whereas no changes were seen in mRNA expression (microarray and qRT-PCR). GLYX-13, unlike ketamine, produced its antidepressant-like effect when injected directly into the medial prefrontal cortex (MPFC). These results suggest that GLYX-13 produces an antidepressant-like effect without the side effects seen with ketamine at least in part by directly modulating NR2B-containing NMDARs in the MPFC. Furthermore, the enhancement of 'metaplasticity' by both GLYX-13 and ketamine may help explain the long-lasting antidepressant effects of these NMDAR modulators. GLYX-13 is currently in a Phase II clinical development program for treatment-resistant depression.
The COVID-19 global pandemic has upended nearly every medical discipline, dramatically impacted patient care and has had far-reaching effects on surgeon education. In many areas of the country, ...elective orthopedic surgery has completely stopped to ensure that resources are available for the critically ill and to minimize the spread of disease. COVID-19 is forcing many around the world to re-evaluate existing processes and organizations and adapt to carry out business, of which medicine and education are not immune. Most national and international orthopedic conferences, training programs, and workshops have been postponed or canceled, and we are now critically evaluating the delivery of education to our colleagues as well as residents and fellows. This article describes the evolution of orthopedic education and significant paradigm shifts necessary to continue to teach ourselves and the future leaders of our noble profession.
Abstract Advocates for navigated (NAV) total hip arthroplasty (THA) emphasize the potential for improved component placement. We reviewed published literature to investigate the claim of increased ...precision of acetabular component placement in navigated THA compared to conventional (N-NAV) THA. Major medical and publishers' databases were searched, making no restrictions for study type, yet restricting results to English-language sources. Nine studies of varying methodological quality involving 1479 THA with a mean age of 59.10 years were included. There was no statistically significant difference in mean acetabular component abduction and anteversion angles between the NAV and N-NAV groups. There was a statistically significant difference in the incidence of acetabular component placement in the “safe zone,” with NAV having significantly more “safe placements” than N-NAV, regardless of the chosen safe zone. In addition, NAV had significantly fewer dislocations than N-NAV. These outcomes demonstrate the possible patient benefit from navigation and resulting tighter control of component position.
Dual mobility (DM) refers to a now widely available option for total hip articulation. DM implants feature a small inner head, a hard bearing, that connects via a taper fit onto the femoral trunnion. ...This head freely rotates but is encased inside a larger, outer polyethylene head that articulates with a smooth acetabular component.
DM acetabular components are available in the form of a monoblock shell or as a liner that is impacted into a modular shell, providing a metal articulation for the polyethylene outer head.
DM is designed to increase hip stability by providing the arthroplasty construct with a higher jump distance, head-to-neck ratio, and range of motion prior to impingement.
The use of DM in total hip arthroplasty continues to increase in the United States for both primary and revision arthroplasty. Surgeons should be aware of the potential benefits and pitfalls.
Long-term data are lacking, especially for modular DM implants. Points of concern include a potential for accelerated polyethylene wear, intraprosthetic dislocation, and modular backside fretting corrosion.
Abstract Allogeneic blood transfusions remain common in primary total knee arthroplasty. We reviewed our experience with 2269 consecutive primary total knee arthroplasties in 2069 patients over a 3.5 ...year period. In our cohort, 1838 received no TXA, 330 received TXA via IV infusion, and 130 had TXA applied topically. The need for blood transfusion, as well as hematocrit levels immediately after surgery in the recovery room and the day of discharge were recorded. Tranexamic acid infusion demonstrated a statistically significant decrease in blood transfusion ( P = 0.001), as did topical application of TXA ( P = 0.019). The transfusion rate without TXA was 6.5% (120/1839) but only 0.3% (1/330) with TXA infusion. There were no transfusions (0/130) with topical TXA. Statistical differences were also noted in both immediate post operative and day of discharge hematocrit levels in patients having TXA infusion while those values for patients with TXA irrigation failed to obtain statistical significance. No significant change in the rate of symptomatic deep venous thrombosis or pulmonary embolism was noted.
Approximately 45% of patients with major depressive disorder (MDD) do not remit when treated with biogenic amine antidepressants. Consequently, there is a significant need for antidepressant agents ...with different mechanisms of action. Early proof of concept (POC) studies with such novel agents play a significant role in helping drug developers identify agents and mechanisms of action that merit more intensive research. Studies have demonstrated that high affinity N-methyl-Daspartate (NMDA) receptor blockers (eg, ketamine) can produce rapid antidepressant effects in patients who have not responded to currently available agents, but treatment with these agents is accompanied by psychotomimetic effects that make their use problematic. This column describes a POC study involving GLYX-13, an N-methyl-D-aspartate receptor glycine site functional partial agonist.
In this double-blind, randomized, placebo-controlled study, a single intravenous (IV) dose of GLYX-13 (1, 5, 10, or 30 mg/kg) or placebo was administered to 116 subjects with MDD who had not benefitted from a trial of at least one biogenic amine antidepressant during the current episode. The primary outcome measure was score on the Hamilton Depression Rating Scale-17 (Ham-D17), which was used to rate overall depressive symptoms at baseline and at 24 hours and days 3, 7, 14, and, in some arms, days 21 and 28 after administration.
GLYX-13, 5 or 10 mg/kg IV, reduced depressive symptoms as assessed by the Ham-D17 at days 1 through 7. Onset of action as assessed using the Bech-6 occurred within 2 hours. GLYX-13 did not elicit psychotomimetic or other significant side effects.
In this early POC study, GLYX-13 reduced depressive symptoms within 2 hours and this effect was maintained for 7 days on average in subjects with MDD who had not responded to another antidepressant agent during the current depressive episode. The findings of this study support the hypothesis that modulation of the NMDA receptor is a valid target for the development of antidepressant drugs and the need for additional studies to further evaluate the effects of GLYX-13. POC studies such as the one described here play a pivotal role in allowing drug researchers to decide whether to move forward with larger and more expensive studies, and they enable them to focus available resources on those molecules that appear to have the most therapeutic promise. Based on the POC study described here, a multiple dose study has been completed which showed sustained therapeutic benefit with repeated dosing of GLYX-13 for more than 6 weeks. Phase 3 studies are now being planned.
We developed an IGFBP2-mimetic peptide fragment, JB2, and showed that it promotes basal synaptic structural and functional plasticity in cultured neurons and mice. We demonstrate that JB2 directly ...binds to dendrites and synapses, and its biological activity involves NMDA receptor activation, gene transcription and translation, and IGF2 receptors. It is not IGF1 receptor-dependent. In neurons, JB2 induced extensive remodeling of the membrane phosphoproteome. Synapse and cytoskeletal regulation, autism spectrum disorder (ASD) risk factors, and a Shank3-associated protein network were significantly enriched among phosphorylated and dephosphorylated proteins. Haploinsufficiency of the SHANK3 gene on chromosome 22q13.3 often causes Phelan-McDermid Syndrome (PMS), a genetically defined form of autism with profound deficits in motor behavior, sensory processing, language, and cognitive function. We identified multiple disease-relevant phenotypes in a Shank3 heterozygous mouse and showed that JB2 rescued deficits in synaptic function and plasticity, learning and memory, ultrasonic vocalizations, and motor function; it also normalized neuronal excitability and seizure susceptibility. Notably, JB2 rescued deficits in the auditory evoked response latency, alpha peak frequency, and steady-state electroencephalography response, measures with direct translational value to human subjects. These data demonstrate that JB2 is a potent modulator of neuroplasticity with therapeutic potential for the treatment of PMS and ASD.
PDF
