Racial and ethnic differences in the pharmacologic management of osteoarthritis: rapid systematic review.

Background: Racial and ethnic disparities in osteoarthritis (OA) patients' disease experience may be related to marked differences in the utilization and prescription of pharmacologic treatments. Objectives: The main objective of this rapid systematic review was to evaluate studies that examined race/ethnic differences in the use of pharmacologic treatments for OA. Data sources and methods: A literature search (PubMed and Embase) was ran on 25 February 2022. Studies that evaluated race/ethnic differences in the use of OA pharmacologic treatments were included. Two reviewers independently screened titles and abstracts and abstracted data from full-text articles. Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Results: The search yielded 3880 titles, and 17 studies were included in this review. African Americans and Hispanics were more likely than non-Hispanic Whites to use prescription non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for OA. However, compared to non-Hispanic Whites with OA, African Americans and Hispanics with OA were less likely to receive a prescription for cyclooxygenase-2-selective NSAIDs and less likely to report the use of joint health supplements (i.e. glucosamine and chondroitin sulfate). There were minimal/no significant race/ethnic differences in the patient-reported use of the following OA therapies: acetaminophen, opioids, and other complementary/alternative medicines (vitamins, minerals, and herbs). There were also no significant race differences in the receipt of intra-articular therapies (i.e. glucocorticoid or hyaluronic acid). However, there is limited evidence to suggest that African Americans may be less likely than Whites to receive opioids and intra-articular therapies in some OA patient populations. Conclusion: This systematic review provides an overview of the current pharmacologic options for OA, with a focus on race and ethnic differences in the use of such medical therapies.

Development and Validation of a Closed-Loop Functional Electrical Stimulation-Based Controller for Gait Rehabilitation Using a Finite State Machine Model.

Functional electrical stimulation (FES) can be used to initiate lower limb muscle contractions and has been widely applied in gait rehabilitation. Establishing the correct timing of FES activation during each phase of the gait (walking) cycle remains challenging as most FES systems rely on open-loop control, whereby the controller receives no feedback about joint kinematics and instead relies on predetermined/timed muscle stimulation. The objective of this study was to develop and validate a closed-loop FES-based control solution for gait rehabilitation using a finite state machine (FSM) model. A two-phased study approach was taken: (1) Experimentally-Informed Study: A neuromuscular-derived FSM model was developed to drive closed-loop FES-based control for gait rehabilitation. The finite states were determined using electromyography and joint kinematics data of 12 non-disabled adults, collected during treadmill walking. The gait cycles were divided into four states, namely: swing-to-stance, push off, pre-swing, and toe up. (2) Simulation Study: A closed-loop FES-based control solution that employed the resulting FSM model, was validated through comparisons of neuro-musculo-skeletal computer simulations of impaired versus healthy gait. This closed-loop controller yielded steadier simulated impaired gait, in comparison to an open-loop alternative. The simulation results confirmed that accurate timing of FES activation during the gait cycle, as informed by kinematics data, is important to natural gait retraining. The closed-loop FES-based solution, introduced in this study, contributes to the repository of gait rehabilitation control options and offers the advantage of being simplistic to implement. Furthermore, this control solution is expected to integrate well with powered exoskeleton technologies.

Acute heat exposure protects against endothelial ischemia-reperfusion injury in aged humans.

Nonpharmacological therapies that protect against endothelial ischemia-reperfusion injury (I/R) remain limited in aged adults. Acute heat exposure protects against endothelial I/R injury in young adults, but its efficacy has never been explored in aged adults. Therefore, we tested the hypothesis that acute heat exposure would prevent the attenuation of endothelium-dependent vasodilation after I/R injury in aged adults. Nine (2 men, 69 ± 8 yr) aged adults were exposed to a thermoneutral control condition or whole body passive heating (water-perfused suit) sufficient to increase body core temperature by 1.2°C. Experiments were separated by at least 7 days. Heat exposure was always performed first to time match the thermoneutral control condition. Endothelium-dependent vasodilation was assessed via flow-mediated dilation of the brachial artery before (pre-I/R) and after I/R injury (post-I/R), which was induced by 20 min of arm ischemia followed by 20 min of reperfusion. Flow-mediated dilation was reduced following I/R injury for the thermoneutral control condition (pre-I/R, 4.5 ± 2.9% vs. post-I/R, 0.9 ± 2.8%, P < 0.01), but was well maintained with prior heat exposure (pre-I/R, 4.4 ± 2.8% vs. post-I/R, 3.5 ± 2.8%, P = 0.5). Taken together, acute heat exposure protects against endothelial I/R injury in aged adults. These results highlight the therapeutic potential of heat therapy to prevent endothelial dysfunction associated with I/R injury in aged adults who are most at risk for an ischemic event.

Acute heat exposure improves microvascular function in skeletal muscle of aged adults.

Acute heat exposure improves microvascular function in aged adults as assessed using reactive hyperemia. The cutaneous and skeletal muscle microcirculations are thought to contribute to this response, but this has never been confirmed due to the methodological challenges associated with differentiating blood flow between these vascular beds. We hypothesized that acute hot water immersion would improve endothelial-dependent, but not endothelial-independent vasodilation in the microcirculation of the vastus lateralis muscle in healthy aged adults. Participants (70 ± 5 yr) were immersed for 60 min in thermoneutral (36°C) or hot (40°C) water. Ninety minutes following immersion, skeletal muscle microdialysis was used to bypass the cutaneous circulation and directly assess endothelial-dependent and endothelial-independent vasodilation by measuring the local hyperemic response to graded infusions of acetylcholine (ACh, 27.5 and 55.0 mM) and sodium nitroprusside (SNP, 21 and 42 mM), respectively. The hyperemic response to 27.5 mM ACh did not differ between thermal conditions (P = 0.9). However, the hyperemic response to 55.0 mM ACh was increased with prior hot water immersion (thermoneutral immersion, 43.9 ± 23.2 mL/min/100 g vs. hot water immersion, 66.5 ± 25.5 mL/min/100 g; P < 0.01). Similarly, the hyperemic response to 21 mM SNP did not differ between thermal conditions (P = 0.3) but was increased following hot water immersion with the infusion of 42 mM SNP (thermoneutral immersion, 48.8 ± 25.6 mL/min/100 g vs. hot water immersion, 90.7 ± 53.5 mL/min/100 g; P < 0.01). These data suggest that acute heat exposure improves microvascular function in skeletal muscle of aged humans.NEW & NOTEWORTHY Acute heat exposure improves microvascular function in aged adults as assessed using reactive hyperemia. The cutaneous and skeletal muscle microcirculations are thought to contribute to this response, but this has never been confirmed due to the methodological challenges associated with differentiating blood flow between these vascular beds. Using the microdialysis technique to bypass the cutaneous circulation, we demonstrated that heat exposure improves endothelial-dependent and endothelial-independent vasodilation in the microcirculation of skeletal muscle in aged humans.

Shear stress induced by acute heat exposure is not obligatory to protect against endothelial ischemia-reperfusion injury in humans.

Acute heat exposure protects against endothelial ischemia-reperfusion (I/R) injury in humans. However, the mechanism/s mediating this protective effect remain unclear. We tested the hypothesis that inhibiting the increase in shear stress induced by acute heat exposure would attenuate the protection of endothelial function following I/R injury. Nine (3 women) young healthy participants were studied under three experimental conditions: 1) thermoneutral control; 2) whole body heat exposure to increase body core temperature by 1.2°C; and 3) heat exposure + brachial artery compression to inhibit the temperature-dependent increase in shear stress. Endothelial function was assessed via brachial artery flow-mediated dilatation before (pre-I/R) and after (post-I/R) 20 min of arm ischemia followed by 20 min of reperfusion. Brachial artery shear rate was increased during heat exposure (681 ± 359 s-1), but not for thermoneutral control (140 ± 63 s-1; P < 0.01 vs. heat exposure) nor for heat + brachial artery compression (139 ± 60 s-1; P < 0.01 vs. heat exposure). Ischemia-reperfusion injury reduced flow-mediated dilatation following thermoneutral control (pre-I/R, 5.5 ± 2.9% vs. post-I/R, 3.8 ± 2.9%; P = 0.06), but was protected following heat exposure (pre-I/R, 5.8 ± 2.9% vs. post-I/R, 6.1 ± 2.9%; P = 0.5) and heat + arterial compression (pre-I/R, 4.4 ± 2.8% vs. post-I/R, 5.8 ± 2.8%; P = 0.1). Contrary to our hypothesis, our findings demonstrate that shear stress induced by acute heat exposure is not obligatory to protect against endothelial I/R injury in humans.NEW & NOTEWORTHY Acute heat exposure protects against endothelial ischemia-reperfusion injury in humans. However, the mechanism/s mediating this protective effect remain unclear. We utilized arterial compression to inhibit the temperature-dependent increase in brachial artery blood velocity that occurs during acute heat exposure to isolate the contribution of shear stress to the protection of endothelial function following ischemia-reperfusion injury. Our findings demonstrate that shear stress induced by acute heat exposure is not obligatory to protect against endothelial I/R injury.

Bioactive Chemical Composition of Cannabis Extracts and Cannabinoid Receptors.

Cannabis is widely used as a therapeutic drug, especially by patients suffering from psychiatric and neurodegenerative diseases. However, the complex interplay between phytocannabinoids and their targets in the human receptome remains largely a mystery, and there have been few investigations into the relationship between the chemical composition of medical cannabis and the corresponding biological activity. In this study, we investigated 59 cannabis samples used by patients for medical reasons. The samples were subjected to extraction (microwave and supercritical carbon dioxide) and chemical analyses, and the resulting extracts were assayed in vitro using the CB1 and CB2 receptors. Using a partial least squares regression analysis, the chemical compositions of the extracts were then correlated to their corresponding cannabinoid receptor activities, thus generating predictive models that describe the receptor potency as a function of major phytocannabinoid content. Using the current dataset, meaningful models for CB1 and CB2 receptor agonism were obtained, and these reveal the insignificant relationships between the major phytocannabinoid content and receptor affinity for CB1 but good correlations between the two at CB2 receptors. These results also explain the anomalies between the receptor activities of pure phytocannabinoids and cannabis extracts. Furthermore, the models for CB1 and CB2 agonism in cannabis extracts predict the cannabinoid receptor activities of individual phytocannabinoids with reasonable accuracy. Here for the first time, we disclose a method to predict the relationship between the chemical composition, including phytocannabinoids, of cannabis extracts and cannabinoid receptor responses.

The effect of thermal therapy on the blood-brain barrier and blood-tumor barrier.

The blood-brain and blood-tumor barriers represent highly specialized structures responsible for tight regulation of molecular transit into the central nervous system. Under normal circumstances, the relative impermeability of the blood-brain barrier (BBB) protects the brain from circulating toxins and contributes to a brain microenvironment necessary for optimal neuronal function. However, in the context of tumors and other diseases of central nervous system, the BBB and the more recently appreciated blood-tumor barrier (BTB) represent barriers that prevent effective drug delivery. Overcoming both barriers to optimize treatment of central nervous system diseases remains the subject of intense scientific investigation. Although many newer technologies have been developed to overcome these barriers, thermal therapy, which dates back to the 1890 s, has been known to disrupt the BBB since at least the early 1980s. Recently, as a result of several technological advances, laser interstitial thermal therapy (LITT), a method of delivering targeted thermal therapy, has gained widespread use as a surgical technique to ablate brain tumors. In addition, accumulating evidence indicates that laser ablation may also increase local BBB/BTB permeability after treatment. We herein review the structure and function of the BBB and BTB and the impact of thermal injury, including LITT, on barrier function.

Magnetic seizure therapy (MST) for major depressive disorder.

Electroconvulsive therapy (ECT) is effective for major depressive disorder (MDD) but its effects on memory limit its widespread use. Magnetic seizure therapy (MST) is a potential alternative to ECT that may not adversely affect memory. In the current trial, consecutive patients with MDD consented to receive MST applied over the prefrontal cortex according to an open-label protocol. Depressive symptoms and cognition were assessed prior to, during and at the end of treatment. Patients were treated two to three times per week with high-frequency MST (i.e., 100 Hz) (N = 24), medium frequency MST (i.e., 60 or 50 Hz) (N = 26), or low-frequency MST (i.e., 25 Hz MST) (N = 36) using 100% stimulator output. One hundred and forty patients were screened; 86 patients with MDD received a minimum of eight treatments and were deemed to have an adequate course of MST; and 47 completed the trial per protocol, either achieving remission (i.e., 24-item Hamilton Rating Scale for Depression score <10 and a relative reduction of >60% at two consecutive assessments; n = 17) or received a maximum of 24 sessions (n = 30). High-frequency (100 Hz) MST produced the highest remission rate (33.3%). Performance on most cognitive measures remained stable, with the exception of significantly worsened recall consistency of autobiographical information and significantly improved brief visuospatial memory task performance. Under open conditions, MST led to clinically meaningful reduction in depressive symptoms in patients with MDD and produced minimal cognitive impairment. Future studies should compare MST and ECT under double-blind randomized condition.

Acute lower leg hot water immersion protects macrovascular dilator function following ischaemia-reperfusion injury in humans.

NEW FINDINGS: • What is the central question of this study? What is the effect of lower leg hot water immersion on vascular ischaemia-reperfusion injury induced in the arm of young healthy humans? • What is the main finding and its importance? Lower leg hot water immersion successfully protects against vascular ischaemia-reperfusion injury in humans. This raises the possibility that targeted heating of the lower legs may be an alternative therapeutic approach to whole-body heating that is equally efficacious at protecting against vascular ischaemia-reperfusion injury. ABSTRACT: Reperfusion that follows a period of ischaemia paradoxically reduces vasodilator function in humans and contributes to the tissue damage associated with an ischaemic event. Acute whole-body hot water immersion protects against vascular ischaemia-reperfusion (I-R) injury in young healthy humans. However, the effect of acute lower leg heating on I-R injury is unclear. Therefore, the purpose of this study was to test the hypothesis that, compared with thermoneutral control immersion, acute lower leg hot water immersion would prevent the decrease in macro- and microvascular dilator functions following I-R injury in young healthy humans. Ten young healthy subjects (5 female) immersed their lower legs into a circulated water bath for 60 min under two randomized conditions: (1) thermoneutral control immersion (∼33°C) and (2) hot water immersion (∼42°C). Macrovascular (brachial artery flow-mediated dilatation) and microvascular (forearm reactive hyperaemia) dilator functions were assessed using Doppler ultrasound at three time points: (1) pre-immersion, (2) 60 min post-immersion, and (3) post-I/R (20 min of arm ischaemia followed by 20 min of reperfusion). Ischaemia-reperfusion injury reduced macrovascular dilator function following control immersion (pre-immersion 6.0 ± 2.1% vs. post-I/R 3.6 ± 2.1%; P < 0.05), but was well-maintained with prior hot water immersion (pre-immersion 5.8 ± 2.1% vs. post-I/R 5.3 ± 2.1%; P = 0.8). Microvascular dilator function did not differ between conditions or across time. Taken together, acute lower leg hot water immersion prevents the decrease in macrovascular dilator function that occurs following I-R injury in young healthy humans.

Mice lacking neuronal calcium sensor-1 show social and cognitive deficits.

Neuronal calcium sensor-1 or Frequenin is a calcium sensor widely expressed in the nervous system, with roles in neurotransmission, neurite outgrowth, synaptic plasticity, learning, and motivated behaviours. Neuronal calcium sensor-1 has been implicated in neuropsychiatric disorders including autism spectrum disorder, schizophrenia, and bipolar disorder. However, the role of neuronal calcium sensor-1 in behavioural phenotypes and brain changes relevant to autism spectrum disorder have not been evaluated. We show that neuronal calcium sensor-1 deletion in the mouse leads to a mild deficit in social approach and impaired displaced object recognition without affecting social interactions, behavioural flexibility, spatial reference memory, anxiety-like behaviour, or sensorimotor gating. Morphologically, neuronal calcium sensor-1 deletion leads to increased dendritic arbour complexity in the frontal cortex. At the level of hippocampal synaptic plasticity, neuronal calcium sensor-1 deletion leads to a reduction in long-term potentiation in the dentate gyrus, but not area Cornu Ammonis 1. Metabotropic glutamate receptor-induced long-term depression was unaffected in both dentate and Cornu Ammonis 1. These studies identify roles for neuronal calcium sensor-1 in specific subregions of the brain including a phenotype relevant to neuropsychiatric disorders.

Glioblastoma Treated With Magnetic Resonance Imaging-Guided Laser Interstitial Thermal Therapy: Safety, Efficacy, and Outcomes.

BACKGROUND: Despite the multitude of available treatments, glioblastoma (GBM) remains an aggressive and uniformly fatal tumor. Laser interstitial thermal therapy (LITT) is a novel, minimally invasive treatment that holds promise for treating patients with GBM who are not candidates for traditional open craniotomy. However, due to the recent introduction of LITT into clinical practice, large series that evaluate safety and long-term outcomes after LITT are lacking. OBJECTIVE: To present our institution's series of over 50 GBM patients treated with LITT, with regard to safety, efficacy, and outcomes. METHODS: We performed a retrospective descriptive study of patients with histologically proven GBM who underwent LITT. Data collected included demographics, tumor location and volume, tumor genetic markers, treatment volume, perioperative complications, and long-term follow-up data. RESULTS: We performed 58 LITT treatments for GBM in 54 patients over 5.5 yr. Forty-one were recurrent tumors while 17 were frontline treatments. Forty GBMs were lobar in location, while 18 were in deep structures (thalamus, insula, corpus callosum). Average tumor volume was 12.5 ± 13.4 cm3. Average percentage of tumor treated with the yellow thermal damage threshold (TDT) line (dose equivalent of 43°C for 2 min) was 93.3% ± 10.6%, and with the blue TDT line (dose equivalent of 43°C for 10 min) was 88.0% ± 14.2%. There were 7 perioperative complications (12%) and 2 mortalities (3.4%). Median overall survival after LITT for the total cohort was 11.5 mo, and median progression-free survival 6.6 mo. CONCLUSION: LITT appears to be a safe and effective treatment for GBM in properly selected patients.

Findings on the heavy metal content in herbal drugs and essential oils - an update.

In this contribution, data for 7 elemental impurities originating from quality control analysis of manufacturers of herbal products is evaluated in light of the current requirements of the European Pharmacopoeia (Ph. Eur.) and the European legislative framework. The data shows that the Ph. Eur. limits set for cadmium, lead and mercury in herbal drugs are in principle still appropriate. The probability of herbal drugs exceeding the limits for arsenic, cobalt, nickel and vanadium (based on the ICH Q3D guideline for elemental impurities) appears to be very low, and consequently, it is proposed that general limits for these elements in herbal drugs in the Ph. Eur. are not required. For essential oils, there does not appear to be a risk of heavy metal contamination and a general test on heavy metals is not considered necessary.

Mobile Applications for Allergic Rhinitis.

OBJECTIVE: To study and review the currently available mobile applications relating to allergic rhinitis. METHODS: The Apple and Google mobile app stores were queried with search terms relating to allergic rhinitis. Apps were assigned to categories and analyzed based on description and characteristics such as popularity, reviews, cost, platform, and physician involvement in development. RESULTS: A total of 72 apps related to allergic rhinitis were identified. Fifty-four apps were unique, with 18 apps found on both operating systems. Forty (55.5%) apps were available in the Apple App store, and 32 (44.4%) apps were available in the Google Play app store. They were grouped into the following categories: patient education (18; 25%), journals (15; 20.8%), symptom tracking (14; 19.4%), clinical/private practice (13; 18.1%), pollen forecast (7; 9.7%), medical education (4; 5.6%), and other (1; 1.4%). The majority of apps were free of charge (67; 93.1%), with paid apps ranging from $1.47 to $4.99. Apps that were reviewed had an average rating of 3.9 out of 5. Physicians were involved in the development of 37 (51.4%) apps. CONCLUSIONS: The collection of mobile apps developed for allergic rhinitis includes those for both educational and clinical use. Mobile apps may have an increasing role in otolaryngic allergy and rhinology practices in the future. Thus, continued research is warranted to determine the best way to ensure the accuracy and quality of app content as well as the extent mobile apps can benefit allergic rhinitis patients.

Pyruvate-enriched resuscitation for shock.

This commentary addresses the recent retraction of an article which reported favorable outcomes in septic patients treated with intravenous pyruvate. The retracted report was cited in the authors' recent minireview on the cellular mechanisms and clinical application of pyruvate to improve cardiac performance. Because the retracted article reports pyruvate-enhanced resuscitation of critically ill patients, the authors wish to inform the readership, especially critical care providers, that this particular clinical application of pyruvate is not now supported by robust evidence. After discussing the retraction's implications for the clinical application of pyruvate-enriched resuscitation for sepsis, this commentary summarizes the extensive preclinical evidence of the efficacy and mechanisms of pyruvate resuscitation in animal models of hemorrhagic and septic shock, which argues for renewed clinical investigation of pyruvate-enriched resuscitation. Impact statement This commentary addresses the recent retraction of a clinical report of significant benefits of intravenous pyruvate resuscitation in septic patients, including sharply lowered mortality and decreased circulating pro-inflammatory cytokines, which was cited in the authors' minireview in Experimental Biology and Medicine. The potential implications of the retraction, and the extensive preclinical evidence supporting the use of pyruvate-enriched resuscitation for shock states, are summarized and discussed.

Trunk Stability Enabled by Noninvasive Spinal Electrical Stimulation after Spinal Cord Injury.

Electrical neuromodulation of spinal networks improves the control of movement of the paralyzed limbs after spinal cord injury (SCI). However, the potential of noninvasive spinal stimulation to facilitate postural trunk control during sitting in humans with SCI has not been investigated. We hypothesized that transcutaneous electrical stimulation of the lumbosacral enlargement can improve trunk posture. Eight participants with non-progressive SCI at C3-T9, American Spinal Injury Association Impairment Scale (AIS) A or C, performed different motor tasks during sitting. Electromyography of the trunk muscles, three-dimensional kinematics, and force plate data were acquired. Spinal stimulation improved trunk control during sitting in all tested individuals. Stimulation resulted in elevated activity of the erector spinae, rectus abdominis, and external obliques, contributing to improved trunk control, more natural anterior pelvic tilt and lordotic curve, and greater multi-directional seated stability. During spinal stimulation, the center of pressure (COP) displacements decreased to 1.36 ± 0.98 mm compared with 4.74 ± 5.41 mm without stimulation (p = 0.0156) in quiet sitting, and the limits of stable displacement increased by 46.92 ± 35.66% (p = 0.0156), 36.92 ± 30.48% (p = 0.0156), 54.67 ± 77.99% (p = 0.0234), and 22.70 ± 26.09% (p = 0.0391) in the forward, backward, right, and left directions, respectively. During self-initiated perturbations, the correlation between anteroposterior arm velocity and the COP displacement decreased from r = 0.5821 (p = 0.0007) without to r = 0.5115 (p = 0.0039) with stimulation, indicating improved trunk stability. These data demonstrate that the spinal networks can be modulated transcutaneously with tonic electrical spinal stimulation to physiological states sufficient to generate a more stable, erect sitting posture after chronic paralysis.

Final results of a phase I dose-escalation, dose-expansion study of adding disulfiram with or without copper to adjuvant temozolomide for newly diagnosed glioblastoma.

Disulfiram has shown promising activity including proteasome inhibitory properties and synergy with temozolomide in preclinical glioblastoma (GBM) models. In a phase I study for newly diagnosed GBM after chemoradiotherapy, we have previously reported our initial dose-escalation results combining disulfiram with adjuvant temozolomide and established the maximum tolerated dose (MTD) as 500 mg per day. Here we report the final results of the phase I study including an additional dose-expansion cohort of disulfiram with concurrent copper. The phase I study consisted of an initial dose-escalation phase of disulfiram 500-1000 mg daily during adjuvant temozolomide, followed by a dose-expansion phase of disulfiram 500 mg daily with copper 2 mg three times daily. Proteasome inhibition was assessed using fluorometric 20S proteasome assay on peripheral blood cell. A total of 18 patients were enrolled: 7 patients received 500 mg disulfiram, 5 patients received 1000 mg disulfiram, and 6 patients received 500 mg disulfiram with copper. Two dose-limiting toxicities occurred with 1000 mg disulfiram. At disulfiram 500 mg with or without copper, only 1 patient (7%) required dose-reduction during the first month of therapy. Addition of copper to disulfiram did not increase toxicity nor proteasome inhibition. The median progression-free survival was 4.5 months (95% CI 0.8-8.2). The median overall survival (OS) was 14.0 months (95% CI 8.3-19.6), and the 2-year OS was 24%. The MTD of disulfiram at 500 mg daily in combination with adjuvant temozolomide was well tolerated by GBM patients, but 1000 mg daily was not. Toxicity and pharmacodynamic effect of disulfiram were similar with or without concurrent copper. The clinical efficacy appeared to be comparable to historical data. Additional clinical trials to combine disulfiram and copper with chemoradiotherapy or to resensitize recurrent GBM to temozolomide are ongoing.

Structural and Preclinical Studies of Computationally Designed Non-Nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection.

The clinical benefits of HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are hindered by their unsatisfactory pharmacokinetic (PK) properties along with the rapid development of drug-resistant variants. However, the clinical efficacy of these inhibitors can be improved by developing compounds with enhanced pharmacological profiles and heightened antiviral activity. We used computational and structure-guided design to develop two next-generation NNRTI drug candidates, compounds I and II, which are members of a class of catechol diethers. We evaluated the preclinical potential of these compounds in BALB/c mice because of their high solubility (510 µg/ml for compound I and 82.9 µg/ml for compound II), low cytotoxicity, and enhanced antiviral activity against wild-type (WT) HIV-1 RT and resistant variants. Additionally, crystal structures of compounds I and II with WT RT suggested an optimal binding to the NNRTI binding pocket favoring the high anti-viral potency. A single intraperitoneal dose of compounds I and II exhibited a prolonged serum residence time of 48 hours and concentration maximum (Cmax) of 4000- to 15,000-fold higher than their therapeutic/effective concentrations. These Cmax values were 4- to 15-fold lower than their cytotoxic concentrations observed in MT-2 cells. Compound II showed an enhanced area under the curve (0-last) and decreased plasma clearance over compound I and efavirenz, the standard of care NNRTI. Hence, the overall (PK) profile of compound II was excellent compared with that of compound I and efavirenz. Furthermore, both compounds were very well tolerated in BALB/c mice without any detectable acute toxicity. Taken together, these data suggest that compounds I and II possess improved anti-HIV-1 potency, remarkable in vivo safety, and prolonged in vivo circulation time, suggesting strong potential for further development as new NNRTIs for the potential treatment of HIV infection.

Volitional regulation of brain responses to food stimuli in overweight and obese subjects: A real-time fMRI feedback study.

Obese subjects who achieve weight loss show increased functional connectivity between dorsolateral prefrontal cortex (dlPFC) and ventromedial prefrontal cortex (vmPFC), key areas of executive control and reward processing. We investigated the potential of real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback training to achieve healthier food choices by enhancing self-control of the interplay between these brain areas. We trained eight male individuals with overweight or obesity (age: 31.8 ± 4.4 years, BMI: 29.4 ± 1.4 kg/m2) to up-regulate functional connectivity between the dlPFC and the vmPFC by means of a four-day rt-fMRI neurofeedback protocol including, on each day, three training runs comprised of six up-regulation and six passive viewing trials. During the up-regulation runs of the four training days, participants successfully learned to increase functional connectivity between dlPFC and vmPFC. In addition, a trend towards less high-calorie food choices emerged from before to after training, which however was associated with a trend towards increased covertly assessed snack intake. Findings of this proof-of-concept study indicate that overweight and obese participants can increase functional connectivity between brain areas that orchestrate the top-down control of appetite for high-calorie foods. Neurofeedback training might therefore be a useful tool in achieving and maintaining weight loss.

Programmatic Approach to Increasing Osteopathic Medical Student Participation in Research: The TCOM Experience.

Providing medical students with a meaningful research-based educational experience will help them become exemplary physicians and informed consumers of medical research outcomes in the practice of evidence-based medicine. By participating in research projects during medical school, students have the opportunity to study specific fields that interest them in greater depth and develop their written and oral presentation skills. Studies indicate that students who have participated in research and scholarly activities during medical school are at an advantage when matching to their preferred residency. In this article, the authors outline programs and projects that provide opportunities for osteopathic medical students at the University of North Texas Health Science Center Texas College of Osteopathic Medicine to research concepts and conduct hypothesis-driven, hands-on research projects.