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.

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.

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.

Peroxisome injury in multiple sclerosis: protective effects of 4-phenylbutyrate in CNS-associated macrophages.

OBJECTIVES: Multiple sclerosis (MS) is a progressive and inflammatory demyelinating disease of the central nervous system (CNS). Peroxisomes perform critical functions that contribute to CNS homeostasis. We investigated peroxisome injury and mitigating effects of peroxisome-restorative therapy on inflammatory demyelination in models of MS. METHODS: Human autopsied CNS tissues (male and female), human cell cultures and cuprizone-mediated demyelination mice (female) were examined by RT-PCR, western blotting and immunolabeling. The therapeutic peroxisome proliferator, 4-phenylbutyrate (4-PBA) was investigated in vitro and in vivo. RESULTS: White matter from MS patients showed reduced peroxisomal transcript and protein levels, including PMP70, compared to non-MS controls. Cultured human neural cells revealed that human microglia contained abundant peroxisomal proteins. TNF-α-exposed microglia displayed reduced immunolabeling of peroxisomal proteins, PMP70 and PEX11ß, which was prevented with 4-PBA. In human myeloid cells exposed to TNF-α or nigericin, suppression of PEX11ß and catalase protein levels were observed to be dependent on NLRP3 expression. Hindbrains from cuprizone-exposed mice showed reduced Abcd1, Cat, and Pex5l transcript levels, with concurrent increased Nlrp3 and Il1b transcript levels, which was abrogated by 4-PBA. In the central corpus callosum, Iba-1 in CNS-associated macrophages (CAMs) and peroxisomal thiolase immunostaining after cuprizone exposure was increased by 4-PBA. 4-PBA prevented decreased myelin basic protein and neurofilament heavy chain immunoreactivity caused by cuprizone exposure. Cuprizone-induced neurobehavioral deficits were improved by 4-PBA treatment. CONCLUSIONS: Peroxisome injury in CAMs, contributed to neuroinflammation and demyelination that was prevented by 4-PBA treatment. A peroxisome-targeted therapy might be valuable for treating inflammatory demyelination and neurodegeneration in MS.Significance statement:Multiple sclerosis (MS) is a common and disabling disorder of the CNS with no curative therapies for its progressive form. The present studies implicate peroxisome impairment in CNS-associated macrophages (CAMs), which include resident microglia and blood-derived macrophages, as an important contributor to inflammatory demyelination and neuroaxonal injury in MS. We also show that the inflammasome molecule NLRP3 is associated with peroxisome injury in vitro and in vivo, especially in CAMs. Treatment with the peroxisome proliferator 4-phenylbutyrate exerted protective effects with improved molecular, morphological and neurobehavioral outcomes that were associated with a neuroprotective CAM phenotype. These findings offer novel insights into the contribution of peroxisome injury in MS together with preclinical testing of a rational therapy for MS.

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.

Few young athletes meet newly derived age- and activity-relevant functional recovery targets after ACL reconstruction.

PURPOSE: National registry data have established Knee injury and Osteoarthritis Outcome Score (KOOS) functional recovery target values for adults after anterior cruciate ligament (ACL) reconstruction. However, the specificity of these target values for young athletes after ACL reconstruction is unclear. The purpose of this analysis was to (1) derive age- and activity-relevant KOOS functional recovery target values from uninjured young athlete data and (2) determine clinical measures at the time of RTS clearance associated with meeting the newly-derived functional recovery target values in young athletes following ACLR. METHODS: Two hundred and twenty-two young athletes (56 uninjured controls, 17.2 ± 2.4 years, 73% female; 166 after ACL reconstruction, 16.9 ± 2.2 years, 68% female) were included in this cross-sectional analysis from a larger cohort study. Uninjured control participants completed the KOOS, and functional recovery target values were defined as the lower bound of the 95% confidence interval for KOOS subscales. ACL reconstruction participants completed testing within 4 weeks of return-to-sport clearance, including the KOOS, single-leg hop tests, and isometric quadriceps strength. In ACL reconstruction participants, logistic regression was used to determine predictors of meeting all KOOS functional recovery target values (primary outcome) among demographic/injury, hop, and strength data (α ≤ 0.05). RESULTS: KOOS functional recovery target values for each subscale from uninjured athlete data were: Pain ≥ 94, Symptoms ≥ 92, Activities of Daily Living ≥ 97, Sport ≥ 92, and Quality-of-Life ≥ 92. At the time of return-to-sport clearance, ACL reconstruction participants met the KOOS functional recovery targets in the following proportions: Pain, 63%; Symptoms, 42%; Activities of Daily Living, 80%; Sport, 45%; Quality-of-Life, 24%; overall functional recovery (met all subscale targets), 17%. In ACL reconstruction participants, significant predictors of overall functional recovery (primary outcome) were: younger age, hamstring graft, pediatric ACL reconstruction, quadriceps strength limb-symmetry index > 90%, single-hop limb-symmetry index > 90%, and crossover-hop limb-symmetry index > 90%. CONCLUSIONS: KOOS functional recovery target values derived from uninjured young athletes were higher than those previously reported. Small proportions of young athletes following recent RTS clearance after ACLR met these newly-derived functional recovery target values, and factors associated with meeting functional recovery target values included younger age, hamstring autograft and pediatric ACLR, and having > 90% LSI for quadriceps strength and single-leg hop tests. LEVEL OF EVIDENCE: I.

Intranasal anti-caspase-1 therapy preserves myelin and glucose metabolism in a model of progressive multiple sclerosis.

Inflammatory demyelination and axonal injury in the central nervous system (CNS) are cardinal features of progressive multiple sclerosis (MS), and linked to activated brain macrophage-like cells (BMCs) including resident microglia and trafficking macrophages. Caspase-1 is a pivotal mediator of inflammation and cell death in the CNS. We investigated the effects of caspase-1 activation and its regulation in models of MS. Brains from progressive MS and non-MS patients, as well as cultured human oligodendrocytes were examined by transcriptomic and morphological methods. Next generation transcriptional sequencing of progressive MS compared to non-MS patients' normal appearing white matter (NAWM) showed induction of caspase-1 as well as other inflammasome-associated genes with concurrent suppression of neuron-specific genes. Oligodendrocytes exposed to TNFα exhibited upregulation of caspase-1 with myelin gene suppression in a cell differentiation state-dependent manner. Brains from cuprizone-exposed mice treated by intranasal delivery of the caspase-1 inhibitor, VX-765 or its vehicle, were investigated in morphological and molecular studies, as well as by fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging. Cuprizone exposure resulted in BMC and caspase-1 activation accompanied by demyelination and axonal injury, which was abrogated by intranasal VX-765 treatment. FDG-PET imaging revealed suppressed glucose metabolism in the thalamus, hippocampus and cortex of cuprizone-exposed mice that was restored with VX-765 treatment. These studies highlight the caspase-1 dependent interactions between inflammation, demyelination, and glucose metabolism in progressive MS and associated models. Intranasal delivery of an anti-caspase-1 therapy represents a promising therapeutic approach for progressive MS and other neuro-inflammatory diseases.

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

OBJECTIVE: To determine whether the addition of a brief psychologically informed video to traditional physical therapy influenced function (primary aim), pain, and psychological beliefs (secondary aims) among adolescents with patellofemoral pain (PFP). DESIGN: Double-blind randomized controlled trial. SETTING: Outpatient physical therapy clinics of a single pediatric hospital. PARTICIPANTS: Sixty-six adolescents with PFP (14.8±1.7 years old, 65% female). INTERVENTION: Adolescents were randomly assigned to view a brief psychologically informed video (n=34) or control video (n=32). The psychologically informed video targeted pain-related fear and pain catastrophizing, and the control video related basic anatomy and factors involved in PFP. MAIN OUTCOME MEASURES: The primary outcome was change in function (Anterior Knee Pain Scale). Secondary outcomes were change in psychological beliefs (fear-avoidance beliefs, kinesiophobia, pain catastrophizing) and pain. Outcomes were assessed at baseline, immediately post intervention, at 2 weeks, at 6 weeks, and at 3 months. RESULTS: Using a 2-way mixed analysis of variance, change in function in the intervention group was greater than the control group, with a moderate treatment effect noted (P=.001, partial η2=0.1). Post hoc testing revealed that there was a significant interaction between the intervention and time from baseline to 2 weeks, but no interaction was noted between 2 weeks and 3 months. The psychologically informed video significantly reduced maladaptive psychological beliefs (P=.01, η2=0.32). No significant between-group differences in pain were noted. CONCLUSIONS: Incorporating a brief one-time psychologically informed video into standard physical therapy care significantly reduced pain-related fear, reduced pain catastrophizing, and improved function among adolescents with PFP. The immediate effect noted on function did not continue throughout the course of care.

Delivery of the Radionuclide 131I Using Cationic Fusogenic Liposomes as Nanocarriers.

Liposomes are highly biocompatible and versatile drug carriers with an increasing number of applications in the field of nuclear medicine and diagnostics. So far, only negatively charged liposomes with intercalated radiometals, e.g., 64Cu, 99mTc, have been reported. However, the process of cellular uptake of liposomes by endocytosis is rather slow. Cellular uptake can be accelerated by recently developed cationic liposomes, which exhibit extraordinarily high membrane fusion ability. The aim of the present study was the development of the formulation and the characterization of such cationic fusogenic liposomes with intercalated radioactive [131I]I- for potential use in therapeutic applications. The epithelial human breast cancer cell line MDA-MB-231 was used as a model for invasive cancer cells and cellular uptake of [131I]I- was monitored in vitro. Delivery efficiencies of cationic and neutral liposomes were compared with uptake of free iodide. The best cargo delivery efficiency (~10%) was achieved using cationic fusogenic liposomes due to their special delivery pathway of membrane fusion. Additionally, human blood cells were also incubated with cationic control liposomes and free [131I]I-. In these cases, iodide delivery efficiencies remained below 3%.

40 Years of Research on Polybrominated Diphenyl Ethers (PBDEs)-A Historical Overview and Newest Data of a Promising Anticancer Drug.

Polybrominated diphenyl ethers (PBDEs) are a group of molecules with an ambiguous background in literature. PBDEs were first isolated from marine sponges of Dysidea species in 1981 and have been under continuous research to the present day. This article summarizes the two research aspects, (i) the marine compound chemistry research dealing with naturally produced PBDEs and (ii) the environmental toxicology research dealing with synthetically-produced brominated flame-retardant PBDEs. The different bioactivity patterns are set in relation to the structural similarities and dissimilarities between both groups. In addition, this article gives a first structure-activity relationship analysis comparing both groups of PBDEs. Moreover, we provide novel data of a promising anticancer therapeutic PBDE (i.e., 4,5,6-tribromo-2-(2',4'-dibromophenoxy)phenol; termed P01F08). It has been known since 1995 that P01F08 exhibits anticancer activity, but the detailed mechanism remains poorly understood. Only recently, Mayer and colleagues identified a therapeutic window for P01F08, specifically targeting primary malignant cells in a low µM range. To elucidate the mechanistic pathway of cell death induction, we verified and compared its cytotoxicity and apoptosis induction capacity in Ramos and Jurkat lymphoma cells. Moreover, using Jurkat cells overexpressing antiapoptotic Bcl-2, we were able to show that P01F08 induces apoptosis mainly through the intrinsic mitochondrial pathway.

Obese Youth Demonstrate Altered Landing Knee Mechanics Unrelated to Lower-Extremity Peak Torque When Compared With Healthy Weight Youth.

Obese (OB) youth demonstrate altered knee mechanics and worse lower-extremity performance compared with healthy weight (HW) youth. Our objectives were to compare sagittal plane knee landing mechanics between OB and HW youth and to examine the associations of knee and hip extension peak torque with landing mechanics in OB youth. Twenty-four OB and 24 age- and sex-matched HW youth participated. Peak torque was measured and normalized to leg lean mass. Peak knee flexion angle and peak internal knee extension moment were measured during a single-leg hop landing. Paired t tests, Pearson correlation coefficients, and Bonferroni corrections were used. OB youth demonstrated worse performance and lower knee extension (OB: 12.76 [1.38], HW: 14.03 [2.08], P = .03) and hip extension (OB: 8.59 [3.13], HW: 11.10 [2.89], P = .005) peak torque. Furthermore, OB youth demonstrated lower peak knee flexion angles (OB: 48.89 [45.41 to 52.37], HW: 56.07 [52.59 to 59.55], P = .02) and knee extension moments (OB: -1.73 [-1.89 to -1.57], HW: -2.21 [-2.37 to -2.05], P = .0001) during landing compared with HW youth. Peak torque measures were not correlated with peak knee flexion angle nor internal knee extension moment during landing in either group (P > .01). OB youth demonstrated altered landing mechanics compared with HW youth. However, no associations among peak torque measurements and knee landing mechanics were present.

Activation of the executioner caspases-3 and -7 promotes microglial pyroptosis in models of multiple sclerosis.

BACKGROUND: Pyroptosis is a type of proinflammatory regulated cell death (RCD) in which caspase-1 proteolytically cleaves gasdermin D (GSDMD) to yield a cytotoxic pore-forming protein. Recent studies have suggested that additional cell death pathways may interact with GSDMD under certain circumstances to execute pyroptosis. Microglia/macrophages in the central nervous system (CNS) undergo GSDMD-associated pyroptosis in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) but the contribution of other cell death pathways to this phenomenon is unknown. Herein, we tested the hypothesis that multiple RCD pathways underlie microglial pyroptosis in the context of neuroinflammation. METHODS: A siRNA screen of genes with known RCD functions was performed in primary human microglia to evaluate their role in nigericin-induced pyroptosis using supernatant lactate dehydrogenase activity as a read-out of cell lysis. Activation of apoptotic executioner proteins and their contribution to pyroptosis was assessed using semi-quantitative confocal microscopy, high-sensitivity ELISA, immunoblot, cell lysis assays, and activity-based fluorescent probes. Quantification of pyroptosis-related protein expression was performed in CNS lesions from patients with progressive MS and mice with MOG35-55-induced EAE, and in matched controls. RESULTS: Among progressive MS patients, activated caspase-3 was detected in GSDMD immunopositive pyroptotic microglia/macrophages within demyelinating lesions. In the siRNA screen, suppression of caspase-3/7, caspase-1, or GSDMD expression prevented plasma membrane rupture during pyroptosis. Upon exposure to pyroptotic stimuli (ATP or nigericin), human microglia displayed caspase-3/7 activation and cleavage of caspase-3/7-specific substrates (e.g., DFF45, ROCK1, and PARP), with accompanying features of pyroptosis including GSDMD immunopositive pyroptotic bodies, IL-1ß release, and membrane rupture. Pyroptosis-associated nuclear condensation and pyroptotic body formation were suppressed by caspase-3/7 inhibition. Pharmacological and siRNA-mediated inhibition of caspase-1 diminished caspase-3/7 activation during pyroptosis. In mice with EAE-associated neurological deficits, activated caspase-3 colocalized with GSDMD immunopositivity in lesion-associated macrophages/microglia. CONCLUSIONS: Activation of executioner caspases-3/7, widely considered key mediators of apoptosis, contributed to GSDMD-associated microglial pyroptosis under neuroinflammatory conditions. Collectively, these observations highlight the convergence of different cell death pathways during neuroinflammation and offer new therapeutic opportunities in neuroinflammatory disease.

Atypical Prenatal Ultrasound Presentation and Neuropathological Findings in a Neonate With Alpha Thalassemia Major: A Case Report.

Alpha thalassemia major is a hemoglobinopathy caused by the inactivation or deletion of all 4 α-globin alleles. We describe a case of α-thalassemia major with atypical ultrasound and neuropathological findings. The mother had her first prenatal visit at 27 4/7 gestational weeks. Ultrasound revealed a hydropic fetus with multiple anomalies. However, the middle cerebral artery peak systolic velocity (MCA-PSV) suggested that the likelihood of fetal anemia was low. Given the poor prognosis of hydrops fetalis, the parents opted for termination of pregnancy. The neonate died shortly after birth. Autopsy revealed a markedly hydropic female infant with severe limb reduction defects and, in contrast to what was suggested by the prenatal MCA-PSV measurement, unequivocal signs of severe anemia. The brain showed diffuse white matter gliosis. Genetic testing subsequently identified HBA1 and HBA2 deletions, consistent with α-thalassemia major. This case highlights the potential pitfall of MCA-PSV, which is nowadays considered the gold standard for noninvasive detection of fetal anemia. In addition, this is 1 of 2 published case reports detailing neuropathological findings in a fetus or neonate with α-thalassemia major and the first to link α-thalassemia major with diffuse white matter gliosis.

A preliminary evaluation of the associations among functional performance tasks and quality of life in obese and healthy weight youth.

The associations among lower extremity functional performance and quality of life in obese youth are unknown. The aims of this study were to compare lower extremity strength, lower extremity functional performance, and health related quality of life between obese and healthy-weight youth and evaluate the relationships between lower extremity performance and health related quality of life in obese youth. Twenty obese and 20 age and sex matched healthy-weight youth were recruited. Peak torque of the major lower extremity muscles were measured. Functional performance was measured with single leg hop and single leg balance tests. The Paediatric Quality of Life questionnaire's physical and psychosocial health subscales were used. Paired t-tests and multiple regression analyses were performed. Obese youth demonstrated decreased peak torque in all muscles measured (P < 0.05), poorer functional performance (P < 0.05), and worse physical health related quality of life (P < 0.05) compared to healthy-weight youth. Lower extremity functional performance was associated with aspects of quality of life in the obese group (P = 0.002), but not in the healthy-weight group (P < 0.05). These results may assist in encouraging best practices in the promotion of exercise, physical activity, and quality of life in obese youth.

Lower patient-reported function at 2 years is associated with elevated knee cartilage T1rho and T2 relaxation times at 5 years in young athletes after ACL reconstruction.

PURPOSE: The purpose was to test the following hypotheses: (1) magnetic resonance imaging (MRI) markers of early knee cartilage degeneration would be present in the involved limb of young athletes after anterior cruciate ligament reconstruction (ACLR) and (2) poor knee function would be associated with MRI markers of cartilage degeneration. METHODS: Twenty-five young athletes after primary, unilateral ACLR (mean age, 16.7 years) were followed to 5-year post-return-to-sport (RTS) clearance, as a part of a larger, prospective cohort study in young athletes post-ACLR. At 2-year post-RTS, patient-reported knee function was evaluated using the Knee injury and Osteoarthritis Outcome Score (KOOS). At 5-year post-RTS, qualitative MRI sequences (3 T) and quantitative T1rho and T2 maps segmented into six regions at the femur and tibia were performed for the involved and uninvolved knee cartilages. Relaxation times were compared between knees using Holm-corrected paired t tests. Linear regression was used to examine the association between KOOS scores at 2 years and relaxation times at 5 years. RESULTS: Elevated T1rho and T2 relaxation times were observed in the involved knee at the anterior medial femoral condyle compared to the uninvolved knee (p = 0.006, p = 0.024, respectively). Lower KOOS-Pain, KOOS-Symptoms, KOOS-ADL, and KOOS-Sport scores at 2-year post-RTS were associated with higher T1rho or T2 relaxation times in various regions of the involved knee at 5-year post-RTS (all p < 0.05). CONCLUSIONS: MRI markers of early cartilage degeneration were identified in the medial compartment of the involved knee in young athletes 5-year post-RTS after ACLR. Lower KOOS scores at 2-year post-RTS were associated with elevated knee cartilage T1rho and T2 relaxation times at 5-year post-RTS. Evaluating patient-reported function over time after ACLR appears to provide insight into future degenerative changes in the knee cartilage matrix.

Young athletes after ACL reconstruction with quadriceps strength asymmetry at the time of return-to-sport demonstrate decreased knee function 1 year later.

PURPOSE: Quadriceps femoris (QF) strength deficits at return-to-sport (RTS) after ACL reconstruction (ACLR) contribute to decreased knee function at the same time point. However, the impact of QF strength at RTS on longitudinal function has not been examined. The purpose of this study was to test the hypothesis that young athletes after ACLR with QF strength asymmetry at RTS would demonstrate decreased knee-related function and lower proportions of functional recovery at 1 year post-RTS compared to young athletes following ACLR with nearly symmetric QF strength at RTS. METHODS: Participants included 76 young athletes (74% female; mean age at RTS = 17.3 years) after primary, unilateral ACLR, cleared to RTS, and followed for 1 year after RTS. At the time of RTS, QF strength was quantified on an isokinetic dynamometer and a Limb Symmetry Index (LSI) was calculated [(involved/uninvolved) × 100%]. The cohort was subdivided into two groups based on RTS QF LSI: high quadriceps (HQ; LSI ≥ 90%; n = 36) and low quadriceps (LQ; LSI < 85%; n = 36). The cohort was followed for 1 year post-RTS, and knee-related function was assessed using the International Knee Documentation Committee subjective form (IKDC), the Knee Injury and Osteoarthritis Outcome Score (KOOS), and LSI of single-leg hop tests. Functional recovery at 1 year post-RTS was defined as KOOS scores above literature-reported cut-offs. RESULTS: While the HQ group demonstrated higher symmetry on all 1 year post-RTS hop tests, only the triple-hop test (p = 0.020) was found to be statistically different. Similarly, while the HQ group scored higher on all 1 year post-RTS self-reported knee function measures, only differences on the KOOS-Sport/Rec score (p = 0.039) and IKDC score (p = 0.011) were statistically different. Additionally, the HQ group demonstrated higher proportions of functional recovery at 1 year post-RTS than the LQ group on the KOOS-Symptoms (HQ: 88.9%, LQ: 69.4%; p = 0.040) and KOOS-Sport/Rec (HQ: 91.7%, LQ: 69.4%; p = 0.017). CONCLUSIONS: Young athletes after ACLR with QF strength asymmetry at RTS demonstrated decreased knee-related function and lower proportions of functional recovery at 1 year post-RTS. However, group differences did not exceed reported minimal clinically important difference values. Further study is warranted to understand factors that contribute to longitudinal knee function after ACLR. Clinicians should focus on restoring symmetric QF strength at RTS after ACLR, which may promote higher longitudinal knee function. LEVEL OF EVIDENCE: Level II, Prospective cohort study.

Treatment Options for Patellar Tendinopathy: A Systematic Review.

PURPOSE: To compare the efficacy of common invasive and noninvasive patellar tendinopathy (PT) treatment strategies. METHODS: A systematic search was performed in PubMed, Google Scholar, CINAHL, UptoDate, Cochrane Reviews, and SPORTDiscus. Fifteen studies met the following inclusion criteria: (1) therapeutic outcome trial for PT, and (2) Victorian Institute of Sports Assessment was used to assess symptom severity at follow-up. Methodological quality and reporting bias were evaluated with a modified Coleman score and Begg's and Egger's tests of bias, respectively. RESULTS: A total of 15 studies were included. Reporting quality was high (mean Coleman score 86.0, standard deviation 9.7), and there was no systematic evidence of reporting bias. Increased duration of symptoms resulted in poorer outcomes regardless of treatment (0.9% decrease in improvement per additional month of symptoms; P = .004). Eccentric training with or without core stabilization or stretching improved symptoms (61% improvement in the Victorian Institute of Sports Assessment score, 95% confidence interval [CI] 53% to 69%). Surgery in patients refractory to nonoperative treatment also improved symptoms (57%, 95% CI 52% to 62%) with similar outcomes among arthroscopic and open approaches. Results from shockwave (54%, 95% CI 22% to 87%) and platelet-rich plasma (PRP) studies (55%, 95% CI 5% to 105%) varied widely though PRP may accelerate early recovery. Finally, steroid injection provided no benefit (20%, 95% CI -20% to 60%). CONCLUSIONS: Initial treatment of PT can consist of eccentric squat-based therapy, shockwave, or PRP as monotherapy or an adjunct to accelerate recovery. Surgery or shockwave can be considered for patients who fail to improve after 6 months of conservative treatment. Corticosteroid therapy should not be used in the treatment of PT. LEVEL OF EVIDENCE: Level IV, systematic review of Level II-IV studies.