Novel meriolin derivatives potently inhibit cell cycle progression and transcription in leukemia and lymphoma cells via inhibition of cyclin-dependent kinases (CDKs).

A key feature of cancer is the disruption of cell cycle regulation, which is characterized by the selective and abnormal activation of cyclin-dependent kinases (CDKs). Consequently, targeting CDKs via meriolins represents an attractive therapeutic approach for cancer therapy. Meriolins represent a semisynthetic compound class derived from meridianins and variolins with a known CDK inhibitory potential. Here, we analyzed the two novel derivatives meriolin 16 and meriolin 36 in comparison to other potent CDK inhibitors and could show that they displayed a high cytotoxic potential in different lymphoma and leukemia cell lines as well as in primary patient-derived lymphoma and leukemia cells. In a kinome screen, we showed that meriolin 16 and 36 prevalently inhibited most of the CDKs (such as CDK1, 2, 3, 5, 7, 8, 9, 12, 13, 16, 17, 18, 19, 20). In drug-to-target modeling studies, we predicted a common binding mode of meriolin 16 and 36 to the ATP-pocket of CDK2 and an additional flipped binding for meriolin 36. We could show that cell cycle progression and proliferation were blocked by abolishing phosphorylation of retinoblastoma protein (a major target of CDK2) at Ser612 and Thr82. Moreover, meriolin 16 prevented the CDK9-mediated phosphorylation of RNA polymerase II at Ser2 which is crucial for transcription initiation. This renders both meriolin derivatives as valuable anticancer drugs as they target three different Achilles' heels of the tumor: (1) inhibition of cell cycle progression and proliferation, (2) prevention of transcription, and (3) induction of cell death.

Novel meriolin derivatives activate the mitochondrial apoptosis pathway in the presence of antiapoptotic Bcl-2.

Meriolin derivatives represent a new class of kinase inhibitors with a pronounced cytotoxic potential. Here, we investigated a newly synthesized meriolin derivative (termed meriolin 16) that displayed a strong apoptotic potential in Jurkat leukemia and Ramos lymphoma cells. Meriolin 16 induced apoptosis in rapid kinetics (within 2-3 h) and more potently (IC50: 50 nM) than the previously described derivatives meriolin 31 and 36 [1]. Exposure of Ramos cells to meriolin 16, 31, or 36 for 5 min was sufficient to trigger severe and irreversible cytotoxicity. Apoptosis induction by all three meriolin derivatives was independent of death receptor signaling but required caspase-9 and Apaf-1 as central mediators of the mitochondrial death pathway. Meriolin-induced mitochondrial toxicity was demonstrated by disruption of the mitochondrial membrane potential (ΔΨm), mitochondrial release of proapoptotic Smac, processing of the dynamin-like GTPase OPA1, and subsequent fragmentation of mitochondria. Remarkably, all meriolin derivatives were able to activate the mitochondrial death pathway in Jurkat cells, even in the presence of the antiapoptotic Bcl-2 protein. In addition, meriolins were capable of inducing cell death in imatinib-resistant K562 and KCL22 chronic myeloid leukemia cells as well as in cisplatin-resistant J82 urothelial carcinoma and 2102EP germ cell tumor cells. Given the frequent inactivation of the mitochondrial apoptosis pathway by tumor cells, such as through overexpression of antiapoptotic Bcl-2, meriolin derivatives emerge as promising therapeutic agents for overcoming treatment resistance.

From the Total Synthesis of Semi-Viriditoxin, Semi-Viriditoxic Acid and Dimeric Naphthopyranones to their Biological Activities in Burkitt B Cell Lymphoma.

Dimeric naphthopyranones are known to be biologically active, however, for the corresponding monomeric naphthopyranones this information is still elusive. Here the first enantioselective total synthesis of semi-viriditoxic acid as well as the synthesis of semi-viriditoxin and derivatives is reported. The key intermediate in the synthesis of naphthopyranones is an α,ß-unsaturated δ-lactone, which we synthesized in two different ways (Ghosez-cyclization and Grubbs ring-closing metathesis), while the domino-Michael-Dieckmann reaction of the α,ß-unsaturated δ-lactone with an orsellinic acid derivative is the key reaction. A structure-activity relationship study was performed measuring the cytotoxicity in Burkitt B lymphoma cells (Ramos). The dimeric structure was found to be crucial for biological activity: Only the dimeric naphthopyranones showed cytotoxic and apoptotic activity, whereas the monomers did not display any activity at all.

The Influence of Strength and Sport Exposure on Psychological Readiness After ACL Reconstruction.

BACKGROUND: Among young athletes returning to sport after anterior cruciate ligament reconstruction (ACLR), the extent to which psychological readiness is influenced by factors beyond the psychological domain is largely unknown. HYPOTHESIS: Young athletes with recent sport exposure and higher quadriceps strength will demonstrate higher psychological readiness within 8 weeks of medical clearance to return to sport (RTS) after ACLR. STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: Level 3. METHODS: A total of 38 young athletes after primary ACLR completed testing within 8 weeks of medical clearance to RTS. All participants completed isometric knee extension strength testing, in addition to the ACL Return to Sport after Injury (ACL-RSI) questionnaire. Athletes who participated in sport between time of medical clearance to RTS and date of study enrollment were categorized as SPORT-YES. Those who had not yet participated in sports were categorized as SPORT-NO. Multiple linear regression analyses were used to determine differences in ACL-RSI scores based on quadriceps strength and sport exposure status, while adjusting for age and sex. RESULTS: Of the 38 participants, 20 (52.6%) were categorized as SPORT-YES. The regression model estimating overall ACL-RSI score (P < 0.01, adjusted R2 = 0.389) included significant independent contributions from age, sex, and sport exposure variables (age: P = 0.01, ß [95% CI] = -2.01 [-3.54, -0.48]; sex (male): P = 0.02, ß [95% CI] = 12.50 [2.36, 22.64]; strength: P = 0.51, ß [95% CI] = -2.47 [-10.07,5.13]; sport exposure: P < 0.01, ß [95% CI] = 12.89 [3.58, 22.19]). CONCLUSION: In partial accordance with our hypothesis, recent sport exposure was significantly associated with higher ACL-RSI scores among young athletes in the weeks after medical clearance to RTS after ACLR, while quadriceps strength was not. CLINICAL RELEVANCE: Future prospective work is needed to determine the existence and direction of causal relationships between exposure to sport environment and psychological readiness among young athletes after ACLR.

Value of MR arthrography for evaluation of children and adolescents with clinically suspected intraarticular cause of hip pain.

PURPOSE: To evaluate the distribution of intra- and extraarticular MRI findings in children and adolescents with clinically suspected intraarticular cause of hip pain in order to assess the need for additional intraarticular contrast administration. MATERIAL AND METHODS: Database was searched over a period of 34 months retrospectively for consecutive hip MR arthrography in young patients (8-17 years) with suspected intraarticular cause of hip or groin pain. Exclusion criteria were prior hip surgery, follow-up examination due to known intraarticular pathology, incomplete examination, qualitatively non-diagnostic examinations, and missing informed consent. Reports of fellowship-trained MSK radiologists were searched for intraarticular versus extraarticular findings explaining hip or groin pain. RESULTS: Seventy patients (68% female; median age: 14.5 years; range:10.8-16.9 years) were analyzed. No reason for pain was found in 30 (42.9%) hips, extraarticular reasons in 20 (28.6%) cases, intraarticular in 14 (20.0%), and both (intra- and extraarticular) in 6 (8.6%) hips. Most common extraarticular reasons were apophysitis (14.3%), other bony stress reactions (12.9%), intramuscular edema (7%), tendinitis (5.7%), and trochanteric bursitis (4.3%). Labral pathology was the most common intraarticular finding (overall:34.3%; partial tear:15.7%, complete tear:15.7%), most frequent at the anterosuperior position (81.8%). Cartilage defects (1.4%), intraarticular neoplasia (1.4%), and tear of the femoral head ligament (2.8%) were rarely found. Synovitis and loose bodies were not observed. Cam-(37.1%) and pincer-configurations (47.1%) were common while hip dysplasia was rare (5.7%). CONCLUSION: MRI in children and adolescents with hip pain should be done primarily without intraarticular contrast administration since most cases show an extraarticular pain reason or no diagnosis detectable with MRI.

Altered reward network responses to social touch in major depression.

BACKGROUND: Social touch is an integral part of social relationships and has been associated with reward. Major depressive disorder (MDD) is characterized by severe impairments in reward processing, but the neural effects of social touch in MDD are still elusive. In this study, we aimed to determine whether the neural processing of social touch is altered in MDD and to assess the impact of antidepressant therapy. METHODS: Before and after antidepressant treatment, 53 MDD patients and 41 healthy controls underwent functional magnetic resonance imaging (fMRI) while receiving social touch. We compared neural responses to social touch in the reward network, behavioral ratings of touch comfort and general aversion to interpersonal touch in patients to controls. Additionally, we examined the effect of treatment response on those measures. RESULTS: Clinical symptoms decreased after treatment and 43.4% of patients were classified as responders. Patients reported higher aversion to interpersonal touch and lower comfort ratings during the fMRI paradigm than controls. Patients showed reduced responses to social touch in the nucleus accumbens, caudate nucleus and putamen than controls, both before and after treatment. Contrary to our hypotheses, these effects were independent of touch velocity. Non-responders exhibited blunted response in the caudate nucleus and the insula compared to responders, again irrespective of time. CONCLUSIONS: These findings suggest altered striatal processing of social touch in MDD. Persistent dysfunctional processing of social touch despite clinical improvements may constitute a latent risk factor for social withdrawal and isolation.

Gasdermin D activation in oligodendrocytes and microglia drives inflammatory demyelination in progressive multiple sclerosis.

Neuroinflammation coupled with demyelination and neuro-axonal damage in the central nervous system (CNS) contribute to disease advancement in progressive multiple sclerosis (P-MS). Inflammasome activation accompanied by proteolytic cleavage of gasdermin D (GSDMD) results in cellular hyperactivation and lytic death. Using multiple experimental platforms, we investigated the actions of GSDMD within the CNS and its contributions to P-MS. Brain tissues from persons with P-MS showed significantly increased expression of GSDMD, NINJ1, IL-1ß, and -18 within chronic active demyelinating lesions compared to MS normal appearing white matter and nonMS (control) white matter. Conditioned media (CM) from stimulated GSDMD+/+ human macrophages caused significantly greater cytotoxicity of oligodendroglial and neuronal cells, compared to CM from GSDMD-/- macrophages. Oligodendrocytes and CNS macrophages displayed increased Gsdmd immunoreactivity in the central corpus callosum (CCC) of cuprizone (CPZ)-exposed Gsdmd+/+ mice, associated with greater demyelination and reduced oligodendrocyte precursor cell proliferation, compared to CPZ-exposed Gsdmd-/- animals. CPZ-exposed Gsdmd+/+ mice exhibited significantly increased G-ratios and reduced axonal densities in the CCC compared to CPZ-exposed Gsdmd-/- mice. Proteomic analyses revealed increased brain complement C1q proteins and hexokinases in CPZ-exposed Gsdmd-/- animals. [18F]FDG PET imaging showed increased glucose metabolism in the hippocampus and whole brain with intact neurobehavioral performance in Gsdmd-/- animals after CPZ exposure. GSDMD activation in CNS macrophages and oligodendrocytes contributes to inflammatory demyelination and neuroaxonal injury, offering mechanistic and potential therapeutic insights into P-MS pathogenesis.

The Effect of a Psychologically Informed Video Series to Treat Adolescents With Patellofemoral Pain: A Randomized Controlled Trial.

OBJECTIVE: To test whether a series of brief, psychologically informed educational videos added to physical therapy improved function among adolescents with patellofemoral pain. The secondary aims were to assess pain and psychological beliefs. DESIGN: A double-blinded randomized controlled trial. METHODS: Sixty-eight adolescents with patellofemoral pain were randomly assigned to view brief, psychologically informed videos (n = 34) or control videos (n = 34) in addition to usual care physical therapy. The psychologically informed videos targeted fear-avoidance beliefs, kinesiophobia, and pain catastrophizing. The control videos conveyed basic anatomy, biomedical factors, and lower extremity mechanics. Outcomes were assessed at baseline, 3 weeks, 6 weeks (primary end point), and 3 months. The primary outcome was change in the Anterior Knee Pain Scale. Secondary outcomes were changes in Numeric Pain-Rating Scale and psychological beliefs (Modified Fear-Avoidance Beliefs Questionnaire-Physical Activity, Tampa Kinesiophobia Scale-11, and Pain Catastrophizing Scale-Child). RESULTS: Adolescents in the psychologically informed group experienced significantly greater improvements in function (Anterior Knee Pain Scale mean difference = 8 points; 95% CI: 2.2, 13.2; P = .01) and pain (Numeric Pain-Rating Scale mean difference = 1.2 points; 95% CI: 0.1, 2.4; P = .04) at 6 weeks compared to the control group. The psychologically informed group had significantly greater reductions in psychological beliefs over time than the control group (P≤.001; partial η2 = 0.32). CONCLUSION: Incorporating psychologically informed education into physical therapy care improved function, pain, and psychological beliefs to a greater extent than the control group. J Orthop Sports Phys Ther 2023;53(10):1-9. Epub: 14 September 2023. doi:10.2519/jospt.2023.12041.

The Association of Physical Competence With Psychological Response Among Young Athletes at Time of Return to Sport After ACL Reconstruction.

BACKGROUND: The traditional index of return-to-sport (RTS) readiness after anterior cruciate ligament reconstruction (ACLR) is the achievement of physical competence criteria. Emerging research indicates that psychological response and self-perceptions of physical competence may be critical mechanisms for successful RTS among young athletes. HYPOTHESIS: Young athletes with higher actual physical competence (APC) and perceived physical competence (PPC) will demonstrate a more positive psychological response at the time of RTS after ACLR. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A total of 41 young athletes after primary ACLR completed testing within 8 weeks of medical clearance to RTS. APC was measured with isokinetic knee extension strength, single-limb crossover hop for distance, and the Knee injury and Osteoarthritis Outcome Score. PPC was measured with the Athletic Competence subscale of the Self-Perception Profile. Criteria for APC and PPC were based on established age- and activity-relevant cutoff scores. Different constructs of psychological response were assessed with the adapted Sport Motivation Scale, Brief Resilience Scale, and Anterior Cruciate Ligament Return to Sport after Injury (ACL-RSI) total and subscale scores (Emotions, Confidence, and Risk Appraisal). Multiple linear regression analyses were used to determine differences in measures of psychological response based on achievement of APC and PPC, while adjusting for age and sex. RESULTS: Of the 41 participants, 10 (24.4%) met all criteria for APC and 22 (53.7%) met the PPC criteria. The regression models estimating the ACL-RSI score (P < .001; adjusted R2 = 0.331), ACL-RSI Emotions score (P < .001; adjusted R2 = 0.427), and ACL-RSI Risk Appraisal score (P = .013; adjusted R2 = 0.212) were statistically significant. Although APC was not associated with any measure of psychological response, meeting PPC criteria, younger age, and male sex were found to be associated with a more positive psychological readiness to RTS, but not with motivation or resilience. CONCLUSION: Meeting PPC criteria was associated with higher psychological readiness to RTS among young athletes after ACLR, while meeting APC criteria was not associated with any construct of psychological response.

Novel p.Asp27Glu ACTA1 variant features congenital myopathy with finger flexor weakness, cardiomyopathy, and cardiac conduction defects.

Pathogenic variants in the skeletal muscle α-actin 1 gene (ACTA1) cause a spectrum of myopathies with clinical and myopathological diversity. Clinical presentations occur from the prenatal period to adulthood, commonly with proximal-predominant weakness and rarely preferential distal weakness. Myopathological findings are wide-ranging, with nemaline rods being most frequent. Associated cardiomyopathy is rare and conduction defects are not reported. We describe a family with congenital myopathy with prominent finger flexor weakness and cardiomyopathy with cardiac conduction defects. The proband, a 48-year-old Caucasian male, his 73-year-old mother, 41-year-old sister, and 19-year-old nephew presented with prominent finger flexor weakness on a background of neonatal hypotonia and delayed motor milestones. All had progressive cardiomyopathy with systolic dysfunction and/or left ventricular dilation. The proband and sister had intraventricular conduction delay and left anterior fascicular block, respectively. The mother had atrial fibrillation. Muscle biopsy in the proband and sister demonstrated congenital fiber-type disproportion and rare nemaline rods in the proband. A novel dominant variant in ACTA1 (c.81C>A, p.Asp27Glu) segregated within the family. This family expands the genotypic and phenotypic spectrum of ACTA1-related myopathy, highlighting preferential finger flexor involvement with cardiomyopathy and conduction disease. We emphasize early and ongoing cardiac surveillance in ACTA1-related myopathy.

Preventing Osteoarthritis After an Anterior Cruciate Ligament Injury: An Osteoarthritis Action Alliance Consensus Statement.

After an anterior cruciate ligament (ACL) injury, people need secondary prevention strategies to identify osteoarthritis at its earliest stages so that interventions can be implemented to halt or slow the progression toward its long-term burden. The Osteoarthritis Action Alliance formed an interdisciplinary Secondary Prevention Task Group to develop a consensus on recommendations to provide clinicians with secondary prevention strategies that are intended to reduce the risk of osteoarthritis after a person has an ACL injury. The group achieved consensus on 15 out of 16 recommendations that address patient education, exercise and rehabilitation, psychological skills training, graded-exposure therapy, cognitive-behavioral counseling (lacked consensus), outcomes to monitor, secondary injury prevention, system-level social support, leveraging technology, and coordinated care models. We hope this statement raises awareness among clinicians and researchers on the importance of taking steps to mitigate the risk of osteoarthritis after an ACL injury.

Evidence Review for Preventing Osteoarthritis After an Anterior Cruciate Ligament Injury: An Osteoarthritis Action Alliance Consensus Statement.

CONTEXT: The Osteoarthritis Action Alliance formed a secondary prevention task group to develop a consensus on secondary prevention recommendations to reduce the risk of osteoarthritis after a knee injury. OBJECTIVE: Our goal was to provide clinicians with secondary prevention recommendations that are intended to reduce the risk of osteoarthritis after a person has sustained an anterior cruciate ligament injury. Specifically, this manuscript describes our methods, literature reviews, and dissenting opinions to elaborate on the rationale for our recommendations and to identify critical gaps. DESIGN: Consensus process. SETTING: Virtual video conference calls and online voting. PATIENTS OR OTHER PARTICIPANTS: The Secondary Prevention Task Group consisted of 29 members from various clinical backgrounds. MAIN OUTCOME MEASURE(S): The group initially convened online in August 2020 to discuss the target population, goals, and key topics. After a second call, the task group divided into 9 subgroups to draft the recommendations and supportive text for crucial content areas. Twenty-one members completed 2 rounds of voting and revising the recommendations and supportive text between February and April 2021. A virtual meeting was held to review the wording of the recommendations and obtain final votes. We defined consensus as >80% of voting members supporting a proposed recommendation. RESULTS: The group achieved consensus on 15 of 16 recommendations. The recommendations address patient education, exercise and rehabilitation, psychological skills training, graded-exposure therapy, cognitive-behavioral counseling (lacked consensus), outcomes to monitor, secondary injury prevention, system-level social support, leveraging technology, and coordinated care models. CONCLUSIONS: This consensus statement reflects information synthesized from an interdisciplinary group of experts based on the best available evidence from the literature or personal experience. We hope this document raises awareness among clinicians and researchers to take steps to mitigate the risk of osteoarthritis after an anterior cruciate ligament injury.

Understanding Recruitment Yield From Social Media Advertisements and Associated Costs of a Telehealth Randomized Controlled Trial: Descriptive Study.

BACKGROUND: Recruiting study participants for clinical research is a challenging yet essential task. Social media platforms, such as Facebook, offer the opportunity to recruit participants through paid advertisements. These ad campaigns may be a cost-effective approach to reaching and recruiting participants who meet specific study criteria. However, little is known about the extent to which clicks on social media advertisements translate to the actual consent and enrollment of participants who meet the study criteria. Understanding this is especially important for clinical trials conducted remotely, such as telehealth-based studies, which open the possibility to recruit over large geographical areas and are becoming more common for the treatment of chronic health conditions, such as osteoarthritis (OA). OBJECTIVE: The aim of this study was to report on the conversion of clicks on a Facebook advertisement campaign to consent to enrollment in an ongoing telehealth physical therapy study for adults with knee OA, and the costs associated with recruitment. METHODS: This was a secondary analysis using data collected over the first 5 months of an ongoing study of adults with knee OA. The Delaware Physical Exercise and Activity for Knee Osteoarthritis program compares a virtually delivered exercise program to a control group receiving web-based resources among adults with knee OA. Advertisement campaigns were configured on Facebook to reach an audience who could be potentially eligible. Clicking on the advertisement directed potential participants to a web-based screening form to answer 6 brief questions related to the study criteria. Next, a research team member called individuals who met the criteria from the screening form and verbally asked additional questions related to the study criteria. Once considered eligible, an electronic informed consent form (ICF) was sent. We described the number of potential study participants who made it through each of these steps and then calculated the cost per participant who signed the ICF. RESULTS: In sum, between July and November 2021, a total of 33,319 unique users saw at least one advertisement, 9879 clicks were made, 423 web-based screening forms were completed, 132 participants were successfully contacted, 70 were considered eligible, and 32 signed the ICF. Recruitment costed an average of US $51.94 per participant. CONCLUSIONS: While there was a low conversion from clicks to actual consent, 32% (32/100) of the total sample required for the study were expeditiously consented over 5 months with a per-subject cost well below traditional means of recruitment, which ranges from US $90 to US $1000 per participant. TRIAL REGISTRATION: Clinicaltrails.gov NCT04980300; https://clinicaltrials.gov/ct2/show/NCT04980300.

Athletes and Nonathletes Show No Difference in Symptoms or Function Prior to Knee Surgery, but Those With Chronic Symptoms Show Increased Pain Catastrophizing and Kinesiophobia.

PURPOSE: To determine whether preoperative psychological status before outpatient knee surgery is influenced by athletic status, symptom chronicity, or prior surgical history. METHODS: International Knee Documentation Committee subjective scores (IKDC-S), Tegner Activity Scale scores, and Marx Activity Rating Scale scores were collected. Psychological and pain surveys included the McGill pain scale, Pain Catastrophizing Scale, Tampa Scale for Kinesiophobia 11, Patient Health Questionnaire 9, Perceived Stress Scale, New General Self-Efficacy Scale, and Life Orientation Test-Revised for optimism. Linear regression was used to determine the effects of athlete status, symptom chronicity (>6 months or ≤6 months), and history of prior surgery on preoperative knee function, pain, and psychological status after matching for age, sex, and surgical procedure. RESULTS: In total, 497 knee surgery patients (247 athletes, 250 nonathletes) completed a preoperative electronic survey. All patients were age 14 years and older and had knee pathology requiring surgical treatment. Athletes were younger than nonathletes on average (mean [SD], 27.7 [11.4] vs 41.6 [13.5] years; P < .001). The most frequently reported level of play among athletes was intramural or recreational (n = 110, 44.5%). Athletes had higher preoperative IKDC-S scores (mean [SE], 2.5 [1.0] points higher; P = .015) and lower McGill pain scores compared to nonathletes (mean [SE] 2.0 [0.85] points lower; P = .017). After matching for age, sex, athlete status, prior surgery, and procedure type, having chronic symptoms resulted in higher preoperative IKDC-S (P < .001), pain catastrophizing (P < .001), and kinesiophobia scores (P = .044). CONCLUSIONS: Athletes demonstrate no difference in symptom/pain and function scores preoperatively when compared to nonathletes of similar age, sex, and knee pathology, as well as no difference in multiple psychological distress outcomes measures. Patients with chronic symptoms have more pain catastrophizing and kinesiophobia, while those who have had prior knee surgeries have slightly higher preoperative McGill pain score. LEVEL OF EVIDENCE: Level III, cross-sectional analysis of prospective cohort study data.

A Preliminary Investigation into the Neural Correlates of Knee Loading during a Change of Direction Task in Individuals after Anterior Cruciate Ligament Reconstruction.

Background: Central nervous system (CNS) function after ACLR, quantified by the blood oxygen level dependent (BOLD) response, is altered in regions of sensory function during knee movement after ACLR. However, it is unknown how this altered neural response may manifest in knee loading and response to sensory perturbations during sport specific movements. Purpose: To investigate the relationship among CNS function and lower extremity kinetics, under multiple visual conditions, during 180° change of direction task in individuals with a history of ACLR. Methods: Eight participants, 39.3 ± 37.1 months after primary, left ACLR performed repetitive active knee flexion and extension of their involved knee during fMRI scanning. Participants separately performed 3D motion capture analysis of a 180° change of direction task under full vision (FV) and stroboscopic vision (SV) conditions. A neural correlate analysis was performed to associate BOLD signal to knee loading of the left lower extremity. Results: Involved limb peak internal knee extension moment (pKEM) was significantly lower in the SV condition (1.89 ± 0.37 N*m/Kg) compared to the FV condition (2.0 ± 0.34 N*m/Kg) (p = .018). Involved limb pKEM during the SV condition was positively correlated with BOLD signal in the contralateral precuneus and superior parietal lobe (Voxels: 53; p = .017; z-stat max: 6.47; MNI peak: 6, -50, 66). Conclusion: There is a positive association between involved limb pKEM in the SV condition and BOLD response in areas of visual-sensory integration. Activation of contralateral precuneus and superior parietal lobe brain regions may be a strategy to maintain joint loading when vision is perturbed. Level of Evidence: Level 3.

Comparing an Expanded Versus Brief Telehealth Physical Therapist Intervention for Knee Osteoarthritis: Study Protocol for the Delaware PEAK Randomized Controlled Trial.

OBJECTIVE: The purpose of this study is to investigate whether a remotely delivered physical therapist intervention increases physical activity (PA) over 12 weeks, compared with existing web-based resources, in adults with knee osteoarthritis (OA). METHODS: This will be a single-center, randomized controlled trial with 2 parallel arms: (1) the Expanded Intervention (Delaware PEAK [Physical Exercise and Activity for Knee osteoarthritis]), which includes five 45- to 60-minute video conference-based sessions of supervised exercise (strengthening exercises, step goals) that are remotely delivered over 12 weeks by a physical therapist; or (2) the Brief Intervention (control group), a website that includes prerecorded videos directing participants to web-based resources for strengthening, PA, and pain management for knee OA that are freely available. The trial will enroll 100 participants who meet the National Institute for Health and Care Excellence OA clinical criteria (≥45 years old, have activity-related knee pain, and have no morning stiffness or it lasts ≤30 minutes), reside in the contiguous United States (excluding Alaska and Hawaii), and are seeking to be more physically active. Outcomes include PA (time in moderate-to-vigorous and light PA, steps per day), sedentary behaviors, treatment beliefs, and self-efficacy for exercise. Our primary outcome is moderate-to-vigorous PA. Outcomes will be measured at baseline, 12 weeks, and 24 weeks. IMPACT: This protocol focuses on the remote delivery of physical therapy via telehealth to adults with knee OA and comes at a critical time, because the burden of inactivity is of particular concern in this population. If successful, the findings of this work will provide strong support for the broad implementation of Delaware PEAK, highlight the utility of telehealth in physical therapy, and address the critical need to utilize exercise to manage adults with knee OA through physical therapists.

Predictions of total work based on measures of muscle strength and hop performance in individuals after ACL reconstruction.

OBJECTIVES: The purpose of this study was to determine the ability to utilize clinical measures of hop performance and thigh muscle strength to predict total limb work, a measure of cumulative single leg power, in young athletes at the time of return to sport after ACLR. We hypothesized that hop test performance and thigh muscle strength would predict total limb work during a maximal effort repeated vertical single-leg jump and that hop test performance would better predict total limb work during a maximal effort repeated vertical single-leg jump than measures of thigh strength. DESIGN: Cross-sectional study. PARTICIPANTS: Analysis on data from 50 individuals after unilateral ACLR (74% women, age 14-23 years) MAIN OUTCOME MEASURES: Performed 10-s repeated vertical single-leg jump test on a force platform where single limb power and resultant total work were calculated. At the same session, participants completed a clinical single leg hop test battery and thigh strength testing. RESULTS: All clinical measures were associated with total work during the repeated vertical single-leg jump test on the involved and uninvolved limbs, respectfully. After controlling for height and weight, quadriceps femoris peak torque at 180°/s was the strongest predictor of total work for both limbs. On the involved limb, performance on the triple hop test for distance also uniquely contributed to the prediction of total work. CONCLUSIONS: Quadriceps femoris muscle strength and distance hop test performance predict total limb work capacity of the involved limb during a single-leg dynamic task. Optimizing both measures after ACLR may positively impact vital components of sports performance.

Longitudinal hippocampal diffusion-weighted imaging and T2 relaxometry demonstrate regional abnormalities which are stable and predict subfield pathology in temporal lobe epilepsy.

OBJECTIVE: High-resolution (1 mm isotropic) diffusion tensor imaging (DTI) of the hippocampus in temporal lobe epilepsy (TLE) patients has shown patterns of hippocampal subfield diffusion abnormalities, which were consistent with hippocampal sclerosis (HS) subtype on surgical histology. The objectives of this longitudinal imaging study were to determine the stability of focal hippocampus diffusion changes over time in TLE patients, compare diffusion and quantitative T2 abnormalities of the sclerotic hippocampus, and correlate presurgical mean diffusivity (MD) and T2 maps with postsurgical histology. METHODS: Nineteen TLE patients and 19 controls underwent two high-resolution (1 mm isotropic) DTI and 1.1 × 1.1 × 1 mm3  T2 relaxometry scans (in a subset of 16 TLE patients and 9 controls) of the hippocampus at 3T, with a 2.6 ± 0.8 year inter-scan interval. Within-participant hippocampal volume, MD and T2 were compared between the scans. Contralateral hippocampal changes 2.3 ± 1.0 years after surgery and ipsilateral preoperative MD maps versus postoperative subfield histopathology were evaluated in eight patients who underwent surgical resection of the hippocampus. RESULTS: Reduced volume and elevated MD and T2 of sclerotic hippocampi remained unchanged between longitudinal scans. Focal regions of elevated MD and T2 in bilateral hippocampi of HS TLE were detected consistently at both scans. Regions of high MD and T2 correlated and remained consistent over time. Volume, MD, and T2 remained unchanged in postoperative contralateral hippocampus. Regional elevations of MD identified subfield neuron loss on postsurgical histology with 88% sensitivity and 88% specificity. Focal T2 elevations identified subfield neuron loss with 75% sensitivity and 88% specificity. SIGNIFICANCE: Diffusion and T2 abnormalities in ipsilateral and contralateral hippocampi remained unchanged between the scans suggesting permanent microstructural alterations. MD and T2 demonstrated good sensitivity and specificity to detect hippocampal subfield neuron loss on postsurgical histology, supporting the potential that high-resolution hippocampal DTI and T2 could be used to diagnose HS subtype before surgery.

The mycotoxin viriditoxin induces leukemia- and lymphoma-specific apoptosis by targeting mitochondrial metabolism.

Inhibition of the mitochondrial metabolism offers a promising therapeutic approach for the treatment of cancer. Here, we identify the mycotoxin viriditoxin (VDT), derived from the endophytic fungus Cladosporium cladosporioides, as an interesting candidate for leukemia and lymphoma treatment. VDT displayed a high cytotoxic potential and rapid kinetics of caspase activation in Jurkat leukemia and Ramos lymphoma cells in contrast to solid tumor cells that were affected to a much lesser extent. Most remarkably, human hematopoietic stem and progenitor cells and peripheral blood mononuclear cells derived from healthy donors were profoundly resilient to VDT-induced cytotoxicity. Likewise, the colony-forming capacity was affected only at very high concentrations, which provides a therapeutic window for cancer treatment. Intriguingly, VDT could directly activate the mitochondrial apoptosis pathway in leukemia cells in the presence of antiapoptotic Bcl-2 proteins. The mitochondrial toxicity of VDT was further confirmed by inhibition of mitochondrial respiration, breakdown of the mitochondrial membrane potential (ΔΨm), the release of mitochondrial cytochrome c, generation of reactive oxygen species (ROS), processing of the dynamin-like GTPase OPA1 and subsequent fission of mitochondria. Thus, VDT-mediated targeting of mitochondrial oxidative phosphorylation (OXPHOS) might represent a promising therapeutic approach for the treatment of leukemia and lymphoma without affecting hematopoietic stem and progenitor cells.