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While modern high efficacy disease modifying therapies have revolutionized the treatment of relapsing-remitting multiple sclerosis, they are less effective at controlling progressive forms of the disease. Meningeal inflammation is a recognized risk factor for cortical gray matter pathology which can result in disabling symptoms such as cognitive impairment and depression, but the mechanisms linking meningeal inflammation and gray matter pathology remain unclear. Here, we performed magnetic resonance imaging (MRI)-guided spatial transcriptomics in a mouse model of autoimmune meningeal inflammation to characterize the transcriptional signature in areas of meningeal inflammation and the underlying brain parenchyma. We found broadly increased activity of inflammatory signaling pathways at sites of meningeal inflammation, but only a subset of these pathways active in the adjacent brain parenchyma. Subclustering of regions adjacent to meningeal inflammation revealed the subset of immune programs induced in brain parenchyma, notably complement signaling and antigen processing/presentation. Trajectory gene and gene set modeling analysis confirmed variable penetration of immune signatures originating from meningeal inflammation into the adjacent brain tissue. This work contributes a valuable data resource to the field, provides the first detailed spatial transcriptomic characterization in a model of meningeal inflammation, and highlights several candidate pathways in the pathogenesis of gray matter pathology., Competing Interests: SG, SS, SK, JH, MS, PC, PB No competing interests declared, (© 2023, Gadani, Singh et al.)

Background: Nonsurgical management of chronic, degenerative rotator cuff tears (RCTs) can be an effective treatment strategy, but there is limited evidence to support conservative treatment of acute, traumatic RCTs. The objective of this study was to assess clinical outcomes and predictors of treatment success in patients with traumatic RCTs who elected for initial nonoperative treatment., Methods: Patients from a single institution were retrospectively identified using diagnostic codes for traumatic RCTs followed by confirmed initial treatment with ≥2 months of physical therapy. The exclusion criteria included surgery within 2 months of injury and greater than grade I fatty infiltration on magnetic resonance imaging. At minimum 2-year follow-up, patients were contacted by telephone to collect interval surgical history and standardized patient-reported outcomes. Physical therapy was considered to have failed in all those who underwent surgical treatment and those with satisfaction ratings of "moderately dissatisfied" or "very dissatisfied.", Results: Follow-up outcomes were obtained in 40 of 49 patients (82%), with an average follow-up time of 4.2 years. Of the RCTs, 9 (22%) were small (<1 cm), 22 (54%) were medium (>1 cm to <3 cm), and 9 (22%) were large (>3 cm to <5 cm). Grade I fatty infiltration was seen on 25% of magnetic resonance imaging scans (n = 10). Rotator cuff repair was performed in 18 patients (45%) following an average of 6 months of nonoperative treatment (range, 3-12 months). Nonoperative treatment was determined to have failed in 23 of 40 patients (58%) in total. Conservative management was more likely to fail in patients with multiple tendons torn (P = .014). Tear size and retraction were not significantly different between patients who underwent surgery and those who did not. Patients who underwent surgical management had an 83% satisfaction rate at final follow-up compared with a 55% satisfaction rate for patients who did not undergo surgery (P = .054). There was no statistically significant difference in the American Shoulder and Elbow Surgeons score or visual analog scale score between these groups. Although patients who underwent surgery had a higher mean Single Alpha Numeric Evaluation score (86.3 vs. 75.1, P = .041), this difference was below the previously established minimal clinically important difference., Conclusion: Nonoperative treatment remains a viable option for certain patients with traumatic RCTs; however, the results of our study demonstrate a considerable early failure rate. This study further supports historical literature demonstrating reliably successful outcomes with surgical treatment of acute, traumatic RCTs., (Copyright © 2024 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Dance for older adults is increasingly being used to support health and well-being. While dance may be enjoyable for many, understanding its benefits for those with limited physical and cognitive abilities may provide further support for how dance may be used in these contexts. This was a study of Sharing Dance Older Adults , a dance program with remotely streamed sessions. Data were collected from 48 older adults who took part in the On Your Feet version of the program, and from 38 who took part in the In Your Seat version. Measures included interviews, physical fitness tests and surveys on mood, quality of life, and program satisfaction. Physical fitness significantly improved for both groups, unlike for mood, social well-being, or quality of life. This contrasts with qualitative findings, with participants reporting how the program enhanced their mood, social interactions, and quality of life.

Central conducting lymphatic anomaly (CCLA) due to congenital maldevelopment of the lymphatics can result in debilitating and life-threatening disease with limited treatment options. We identified 4 individuals with CCLA, lymphedema, and microcystic lymphatic malformation due to pathogenic, mosaic variants in KRAS. To determine the functional impact of these variants and identify a targeted therapy for these individuals, we used primary human dermal lymphatic endothelial cells (HDLECs) and zebrafish larvae to model the lymphatic dysplasia. Expression of the p.Gly12Asp and p.Gly13Asp variants in HDLECs in a 2‑dimensional (2D) model and 3D organoid model led to increased ERK phosphorylation, demonstrating these variants activate the RAS/MAPK pathway. Expression of activating KRAS variants in the venous and lymphatic endothelium in zebrafish resulted in lymphatic dysplasia and edema similar to the individuals in the study. Treatment with MEK inhibition significantly reduced the phenotypes in both the organoid and the zebrafish model systems. In conclusion, we present the molecular characterization of the observed lymphatic anomalies due to pathogenic, somatic, activating KRAS variants in humans. Our preclinical studies suggest that MEK inhibition should be studied in future clinical trials for CCLA due to activating KRAS pathogenic variants.

Objective: Asian Americans are underutilizing mental health services. The aim of the current systematic review was to identify protective and risk factors of mental health help-seeking patterns among the disaggregated Asian Americans and to classify types of help., Methods: A systematic literature review was conducted using the PRISMA guidelines. The Health Belief Model served as the theoretical framework for this review. Thirty-four articles were reviewed, and the studies investigated one of the following Asian ethnic subgroups: Chinese, Filipino, Asian Indian, Korean, or Vietnamese. Data were extracted based on the study characteristics, sample characteristics, and protective and risk factors to mental health help-seeking patterns., Results: Predisposing factors like female gender, higher levels of English proficiency, and history of mental illness increased the likelihood for help-seeking across several ethnic groups. Interestingly, cues to action and structural factors were under-examined. However, cues to action like having a positive social network did increase the likelihood of using formal support services among Chinese and Filipinx participants. Structural factors like lacking ethnic concordant providers and access to healthcare served as barriers for Korean and Vietnamese participants., Discussion: The findings showed a need for ethnic tailored approaches when supporting mental health help-seeking patterns. Asian ethnic group's immigration status, acculturation level, and psychological barriers to help-seeking should continue to be emphasized. Psychoeducational groups can be beneficial to expand the knowledge base surrounding mental illness and to link group members to culturally responsive resources., (© 2021. W. Montague Cobb-NMA Health Institute.)

Objective : Great strides have been made to conduct intervention studies aimed at increasing colorectal cancer (CRC) screening rates that are informed by sound theoretical frameworks and conducted using rigorous methodologies; however, efforts are still gaining wave to understand the efficacy of theory-based interventions among Asian American (AA) population. The purpose of this study was to report the results of a meta-analysis conducted on the effects of CRC screening interventions. Methods : The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used to evaluate the CRC screening interventions. Literature search was performed on October 2018, and studies published in English and conducted in the United States were eligible for inclusion if they (1) conducted interventions with aims to increase CRC screening rates among AA and (2) utilized a randomized control trial or quasi-experimental study design, (3) reported quantitative screening rates following the intervention, and (4) included a comparison or control group for comparison. No publication year restriction was applied. Result : In total, 14 Odds Ratio (OR) from 16 studies were included in the meta-analysis. Overall, results indicated that AA participants who received the screening interventions aimed at improving screening were 1.78 times more likely to obtain a CRC screening at post-intervention compared to those in the control or comparison group, OR = 1.78 (1.44, 2.11). Conclusion : Understanding the efficacy of interventions designed to promote CRC screening among AA population is imperative to decrease CRC burden and mortality. Although research in this area is limited, this review sheds light on important socio-cultural strategies to developing a CRC screening intervention aimed at increasing screening rates among AA. Findings in this review demonstrate that improvement in screening can be achieved through a variety of ways, but the common feature across all the studies was the culturally responsive foundation of their respective interventions.

C-C motif chemokine receptor 2 (CCR2) is an important mediator of myeloid cell chemotaxis during inflammation and infection. Myeloid cells such as monocytes, macrophages, and neutrophils contribute to host defense during orthopedic implant-associated infections (OIAI), but whether CCR2-mediated chemotaxis is involved remains unclear. Therefore, a Staphylococcus aureus OIAI model was performed by surgically placing an orthopedic-grade titanium implant and inoculating a bioluminescent S. aureus strain in knee joints of wildtype (wt) and CCR2-deficient mice. In vivo bioluminescent signals significantly increased in CCR2-deficient mice compared with wt mice at later time points (Days 14-28), which was confirmed with ex vivo colony-forming unit enumeration. S. aureus γ-hemolysin utilizes CCR2 to induce host cell lysis. However, there were no differences in bacterial burden when the OIAI model was performed with a parental versus a mutant γ-hemolysin-deficient S. aureus strain, indicating that the protection was mediated by the host cell function of CCR2 rather than γ-hemolysin virulence. Although CCR2-deficient and wt mice had similar cellular infiltrates in the infected joint tissue, CCR2-deficient mice had reduced myeloid cells and γδ T cells in the draining lymph nodes. Taken together, CCR2 contributed to host defense at later time points during an OIAI by increasing immune cell infiltrates in the draining lymph nodes, which likely contained the infection and prevented invasive spread., (© 2021 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Ichthyosis follicularis, atrichia, and photophobia syndrome (IFAP syndrome) is a rare, X-linked disorder caused by pathogenic variants in membrane-bound transcription factor protease, site 2 (MBTPS2). Pathogenic MBTPS2 variants also cause BRESHECK syndrome, characterized by the IFAP triad plus intellectual disability and multiple congenital anomalies. Here we present a patient with ichthyosis, sparse hair, pulmonic stenosis, kidney dysplasia, hypospadias, growth failure, thrombocytopenia, anemia, bone marrow fibrosis, and chronic diarrhea found by research-based exome sequencing to harbor a novel, maternally inherited MBTPS2 missense variant (c.766 G>A; (p.Val256Leu)). In vitro modeling supports variant pathogenicity, with impaired cell growth in cholesterol-depleted media, attenuated activation of the sterol regulatory element-binding protein pathway, and failure to activate the endoplasmic reticulum stress response pathway. Our case expands both the genetic and phenotypic spectrum of BRESHECK syndrome to include a novel MBTPS2 variant and cytopenias, bone marrow fibrosis, and chronic diarrhea., (© 2021 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

STRENGTHS-BASED INQUIRY OF RESILIENCY FACTORS AMONG REFUGEES IN METRO VANCOUVER: A comparison of newly-arrived and settled refugees., Objective: To identify the resiliency factors among refugees in the Metro Vancouver area, and compare these factors between newly-arrived and settled refugees., Design: Semi-structured individual interviews., Setting: Vancouver, British Columbia, and surrounding suburban communities., Participants: 13 key informants from resettlement, healthcare, and public education sectors who work closely with refugees, 13 refugees who have resided less than five years in Canada (LTFYRs), and 8 refugees who have resided greater than five years in Canada (GTFYRs). Refugee source countries were Syria, Iraq, Afghanistan, Iran, Kenya, Vietnam, Somalia, and Mexico., Main Findings: Key informants stated that knowledge from this study would help create and improve current supports for refugees, inform policy, increase understanding of refugee perspectives, and promote strengths-based resettlement strategies. Resiliency factors were grouped into themes, which were categorized as internal or external resiliency factors. Internal resiliency factors included fixed characteristics (age at arrival, female gender, and past education/skills), positive coping strategies (acceptance and positivity), proactivity, and integration (personal identity and adaptation). External resiliency factors identified were support systems, employment and finances, living environment, and societal encouragement of refugees. Comparison of responses between LTFYRs and GTFYRs revealed overall consistency in resiliency factors, but with LTFYRs identifying characteristics that assisted with acute integration, such as age at arrival, more often than GTFYRs. Comparison of responses between refugees and key informants revealed that key informants less frequently identified internal resiliency factors., Conclusion: This study qualitatively describes several internal and external resiliency factors of refugees in Vancouver. Awareness and promotion of these resiliency factors in refugee populations, in collaboration with healthcare providers, settlement organizations and education systems, may improve refugee resettlement. These findings will also help generate the groundwork for local interventions that can support refugee resiliency in the population studied., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Researchers have categorized people into four "mouth-behavior" groups based on their oral processing preferences, and claimed that members of those mouth-behavior groups differ in their food texture preferences. If people could be classified into groups based on their liking of different textures, food products could be targeted to specific subgroups, potentially enhancing consumer acceptability. In the first part of our study, we grouped people based on their liking ratings of a wide variety of food textures by asking 288 participants to rate their liking of 106 food texture attributes in an online survey. In the second part of our study, we further examined relationships among individuals' food texture liking ratings, mouth-behavior group membership, and measurements of four oral physiological parameters (saliva flow rate, chewing efficiency, biting force, and particle size sensitivity). One-hundred participants completed the online survey on food texture liking, classified themselves into one of four mouth-behavior groups (Chewers, Crunchers, Smooshers, and Suckers), and were measured for four oral physiological parameters. We refuted the idea that large texture-liking subgroups exist. Although our participants self-categorized themselves into the four mouth-behavior groups similarly to previous researchers, our texture liking measurements did not support the presumed preferences of those mouth-behavior groups. Clustering of participants on their oral physiological measurements produced a "low particle-size sensitivity" cluster, a "high biting force" cluster, a "high saliva flow rate" cluster, and a "low saliva flow and low chewing efficiency" cluster. Neither our texture liking nor our oral physiological measurements predicted membership in the four mouth-behavior groups., (© 2019 Wiley Periodicals, Inc.)

Surgical site infections (SSIs) are commonly caused by Staphylococcus aureus We report that a combination of three monoclonal antibodies (MEDI6389) that neutralize S. aureus alpha-toxin, clumping factor A, and four leukocidins (LukSF, LukED, HlgAB, and HlgCB) plus vancomycin had enhanced efficacy compared with control antibody plus vancomycin in two mouse models of S. aureus SSI. Therefore, monoclonal antibody-based neutralization of multiple S. aureus virulence factors may provide an adjunctive perioperative approach to combat S. aureus SSIs., (Copyright © 2019 American Society for Microbiology.)

Quantitative T1rho magnetic resonance imaging (MRI) can potentially help identify early-stage osteoarthritis (OA) by non-invasively assessing proteoglycan concentration in articular cartilage. T1rho relaxation times are negatively correlated with proteoglycan concentration. Cartilage compresses in response to load, resulting in water exudation, a relative increase in proteoglycan concentration, and a decrease in the corresponding T1rho relaxation times. To date, there is limited information on changes in cartilage composition resulting from daily activity. Therefore, the objective of this study was to quantify changes in tibial cartilage T1rho relaxation times in healthy human subjects following activities of daily living. It was hypothesized that water exudation throughout the day would lead to decreased T1rho relaxation times. Subjects underwent MR imaging in the morning and afternoon on the same day and were free to go about their normal activities between scans. Our findings confirmed the hypothesis that tibial cartilage T1rho relaxation times significantly decreased (by 7%) over the course of the day with loading, which is indicative of a relative increase in proteoglycan concentration. Additionally, baseline T1rho values varied with position within the cartilage, supporting a need for site-specific measurements of T1rho relaxation times. Understanding how loading alters the proteoglycan concentration in healthy cartilage may hold clinical significance pertaining to cartilage homeostasis and potentially help to elucidate a mechanism for OA development. These results also indicate that future studies using T1rho relaxation times as an indicator of cartilage health should control the loading history prior to image acquisition to ensure the appropriate interpretation of the data., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Our objective was to determine the relationship of T1rho and T2 relaxation mapping to the biochemical and biomechanical properties of articular cartilage through selective digestion of proteoglycans and collagens. Femoral condyles were harvested from porcine knee joints and treated with either chondroitinase ABC (cABC) followed by collagenase, or collagenase followed by cABC. Magnetic resonance images were acquired and cartilage explants were harvested for biochemical, biomechanical, and histological analyses before and after each digestion. Targeted enzymatic digestion of proteoglycans with cABC resulted in elevated T1rho relaxation times and decreased sulfated glycosaminoglycan content without affecting T2 relaxation times. In contrast, extractable collagen and T2 relaxation times were increased by collagenase digestion; however, neither was altered by cABC digestion. Aggregate modulus decreased with digestion of both components. Overall, we found that targeted digestion of proteoglycans and collagens had varying effects on biochemical, biomechanical, and imaging properties. T2 relaxation times were altered with changes in extractable collagen, but not changes in proteoglycan. However, T1rho relaxation times were altered with proteoglycan loss, which may also coincide with collagen disruption. Since it is unclear which matrix components are disrupted first in osteoarthritis, both markers may be important for tracking disease progression.

Colorectal cancer (CRC) is one of the top three cancers experienced among Asian American (AA) men and women. One effective way to decrease incidence and mortality from CRC is the adherence of regular CRC screening; however, AA continue to receive the lowest screening rates compared to other racial/ethnic groups. When disaggregating this heterogeneous population, further disparities exist between subgroups. Examination of facilitators and barriers to cancer screening among AA subgroups is fairly recent and the synthesis of this information is limited. As such, a systematic review was conducted examining the facilitators and the barriers among Chinese, Filipino, Korean, and Japanese Americans using a systematic literature review method. The Health Belief Model served as the primary theoretical framework for this study and used to organize and synthesize the facilitators and barriers to CRC screening. In total, 22 articles yielded 29 examinations of each of the AA subgroups. Different facilitators and barriers to screening uptake for each subgroup were revealed; however, consistent across all the subgroups was physician recommendation as a facilitator and participants' unawareness of screening tests and those stating having no problems/symptoms of CRC as a barrier across screening modalities. Tailored approach in outreach and intervention efforts are suggested when achieving to improve CRC screening in AA ethnic subgroups.

Background: The incidence of anterior cruciate ligament (ACL) ruptures is 2 to 4 times higher in female athletes as compared with their male counterparts. As a result, a number of recent studies have addressed the hypothesis that female and male patients sustain ACL injuries via different mechanisms. The efficacy of prevention programs may be improved by a better understanding of whether there are differences in the injury mechanism between sexes. Hypothesis/Purpose: To compare knee positions at the time of a noncontact ACL injury between sexes. It was hypothesized that there would be no differences in the position of injury., Study Design: Controlled laboratory study., Methods: Clinical T2-weighted magnetic resonance imaging (MRI) scans from 30 participants (15 male and 15 female) with a noncontact ACL rupture were reviewed retrospectively. MRI scans were obtained within 1 month of injury. Participants had contusions associated with an ACL injury on both the medial and lateral articular surfaces of the femur and tibia. Three-dimensional models of the femur, tibia, and associated bone bruises were created via segmentation on MRI. The femur was positioned relative to the tibia to maximize bone bruise overlap, thereby predicting the bone positions near the time of the injury. Flexion, valgus, internal tibial rotation, and anterior tibial translation were measured in the predicted position of injury., Results: No statistically significant differences between male and female patients were detected in the position of injury with regard to knee flexion ( P = .66), valgus ( P = .87), internal tibial rotation ( P = .26), or anterior tibial translation ( P = .18)., Conclusion: These findings suggest that a similar mechanism results in an ACL rupture in both male and female athletes with this pattern of bone bruising., Clinical Relevance: This study provides a novel comparison of male and female knee positions at the time of an ACL injury that may offer information to improve injury prevention strategies.

Non-invasive techniques for quantifying early biochemical and biomechanical changes in articular cartilage may provide a means of more precisely assessing osteoarthritis (OA) progression. The goals of this study were to determine the relationship between T1rho magnetic resonance (MR) imaging relaxation times and changes in cartilage composition, cartilage mechanical properties, and synovial fluid biomarker levels and to demonstrate the application of T1rho imaging to evaluate cartilage composition in human subjects in vivo. Femoral condyles and synovial fluid were harvested from healthy and OA porcine knee joints. Sagittal T1rho relaxation MR images of the condyles were acquired. OA regions of OA joints exhibited an increase in T1rho relaxation times as compared to non-OA regions. Furthermore in these regions, cartilage sGAG content and aggregate modulus decreased, while percent degraded collagen and water content increased. In OA joints, synovial fluid concentrations of sGAG decreased and C2C concentrations increased compared to healthy joints. T1rho relaxation times were negatively correlated with cartilage and synovial fluid sGAG concentrations and aggregate modulus and positively correlated with water content and permeability. Additionally, we demonstrated the application of these in vitro findings to the study of human subjects. Specifically, we demonstrated that walking results in decreased T1rho relaxation times, consistent with water exudation and an increase in proteoglycan concentration with in vivo loading. Together, these findings demonstrate that cartilage MR imaging and synovial fluid biomarkers provide powerful non-invasive tools for characterizing changes in the biochemical and biomechanical environments of the joint., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aberrant access to genetic information disrupts cellular homeostasis and can lead to cancer development. One molecular mechanism that regulates access to genetic information includes recognition of histone modifications, which is carried out by protein modules that interact with chromatin and serve as landing pads for enzymatic activities that regulate gene expression. The ING3 tumor suppressor protein contains a plant homeodomain (PHD) that reads the epigenetic code via recognition of histone H3 tri-methylated at lysine 4 (H3K4me3), and this domain is lost or mutated in various human cancers. However, the molecular mechanisms targeting ING3 to histones and the role of this interaction in the cell remain elusive. Thus, we employed biochemical and structural biology approaches to investigate the interaction of the ING3 PHD finger (ING3PHD) with the active transcription mark H3K4me3. Our results demonstrate that association of the ING3PHD with H3K4me3 is in the sub-micromolar range (KD ranging between 0.63 and 0.93 μm) and is about 200-fold stronger than with the unmodified histone H3. NMR and computational studies revealed an aromatic cage composed of Tyr-362, Ser-369, and Trp-385 that accommodate the tri-methylated side chain of H3K4. Mutational analysis confirmed the critical importance of Tyr-362 and Trp-385 in mediating the ING3PHD-H3K4me3 interaction. Finally, the biological relevance of ING3PHD-H3K4me3 binding was demonstrated by the failure of ING3PHD mutant proteins to enhance ING3-mediated DNA damage-dependent cell death. Together, our results reveal the molecular mechanism of H3K4me3 selection by the ING3PHD and suggest that this interaction is important for mediating ING3 tumor suppressive activities., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Background: The motions causing noncontact anterior cruciate ligament (ACL) injury remain unclear. Tibiofemoral bone bruises are believed to be the result of joint impact near the time of ACL rupture. The locations and frequencies of these bone bruises have been reported, but there are limited data quantifying knee position and orientation near the time of injury based on these contusions., Hypothesis: Knee position and orientation near the time of noncontact ACL injury include extension and anterior tibial translation., Study Design: Descriptive laboratory study., Methods: Magnetic resonance images of 8 subjects with noncontact ACL injuries were acquired within 1 month of injury and were subsequently analyzed. All subjects exhibited bruises on both the femur and tibia in both medial and lateral compartments. The outer margins of bone and the bone bruise surfaces were outlined on each image to create a 3-dimensional model of each subject's knee in its position during magnetic resonance imaging (MRI position). Numerical optimization was used to maximize overlap of the bone bruises on the femur and tibia and to predict the position of injury. Flexion angle, valgus orientation, internal tibial rotation, and anterior tibial translation were measured in both the MRI position and the predicted position of injury. Differences in kinematics between the MRI position, which served as an unloaded reference, and the predicted position of injury were compared by use of paired t tests., Results: Flexion angle was near full extension in both the MRI position and the predicted position of injury (8° vs 12°; P = .2). Statistically significant increases in valgus orientation (5°; P = .003), internal tibial rotation (15°; P = .003), and anterior tibial translation (22 mm; P < .001) were observed in the predicted position of injury relative to the MRI position., Conclusion: These results suggest that for the bone bruise pattern studied, landing on an extended knee is a high risk for ACL injury. Extension was accompanied by increased anterior tibial translation (22 mm), internal tibial rotation (15°), and valgus rotation (5°) in the predicted position of injury relative to the MRI position., Clinical Relevance: This study provides novel data characterizing the motions associated with ACL injury, information critical to improving strategies aimed at injury prevention., (© 2015 The Author(s).)

MCs are required for an effective host response during septic peritonitis. Local MC degranulation facilitates neutrophil recruitment, activation, and bacterial killing. However, the role of MCs located distant from the site of infection is unknown. We studied the temporal and spacial degranulation of MCs following CLP-induced septic peritonitis. The functional importance of systemic MC degranulation during infection was evaluated by compartment-specific MC reconstitution. Serum histamine, reflecting MC degranulation, was elevated 4 h after onset of septic peritonitis. Histologic examination revealed progressive MC degranulation in select tissues during the first 24 h of infection. MC-deficient Wsh mice, reconstituted only in the peritoneal compartment, had improved survival after CLP compared with controls. However, reconstitution in peritoneal plus systemic compartments worsened survival after CLP. IL-6 contributed to the detrimental effects of systemic MCs on survival, as mice systemically reconstituted with IL-6(-/-) MCs were more likely to survive than control mice. These results indicate that in contrast to the benefits of local MC activation during infection, systemic MC activation worsens survival during CLP-induced sepsis.

Prior work has shown that transforming growth factor-β (TGF-β) can mediate transition of alveolar type II cells into mesenchymal cells in mice. Evidence this occurs in humans is limited to immunohistochemical studies colocalizing epithelial and mesenchymal proteins in sections of fibrotic lungs. To acquire further evidence that epithelial-to-mesenchymal transition occurs in the lungs of patients with idiopathic pulmonary fibrosis (IPF), we studied alveolar type II cells isolated from fibrotic and normal human lung. Unlike normal type II cells, type II cells isolated from the lungs of patients with IPF express higher levels of mRNA for the mesenchymal proteins type I collagen, α-smooth muscle actin (α-SMA), and calponin. When cultured on Matrigel/collagen, human alveolar type II cells maintain a cellular morphology consistent with epithelial cells and expression of surfactant protein C (SPC) and E-cadherin. In contrast, when cultured on fibronectin, the human type II cells flatten, spread, lose expression of pro- SPC, and increase expression of vimentin, N-cadherin, and α-SMA; markers of mesenchymal cells. Addition of a TGF-β receptor kinase inhibitor (SB431542) to cells cultured on fibronectin inhibited vimentin expression and maintained pro-SPC expression, indicating persistence of an epithelial phenotype. These data suggest that alveolar type II cells can acquire features of mesenchymal cells in IPF lungs and that TGF-β can mediate this process.

Purpose: To evaluate the utility of baseline Stratus optical coherence tomography (OCT; Carl Zeiss Meditec, Dublin, CA) retinal nerve fiber layer (RNFL) normative classification in the prediction of future visual field (VF) loss., Methods: Eighty-eight eyes with suspected glaucoma with abnormal RNFL classification by Stratus OCT were followed up for more than 4 years. VF conversion in three consecutive tests was assessed after baseline Stratus OCT and VF examination. Baseline intraocular pressure, VF global indices, OCT RNFL thickness, and number of abnormal OCT sectors were compared between VF converters (CG) and nonconverters (NCG). Positive and negative predictive values (PPV, NPV) of OCT sectors with abnormal classifications were calculated with respect to VF conversion. Hazard ratios (HRs) of various risk factors, including abnormal OCT classification, with respect to future VF conversion, were determined by use of the Cox proportional hazard model., Results: Twenty-one (23.9%) eyes showed VF conversion during follow-up. Baseline OCT RNFL thickness was significantly lower and the number of abnormal OCT RNFL sectors significantly greater in CG than in NCG patients (P = 0.022 for both). The PPV and NPV of normative OCT RNFL classification was highest in the inferior quadrant (50%, 87.1%, respectively). Baseline VF mean deviation (MD) and the number of abnormal OCT RNFL sectors were both associated with future VF conversion (HR, 0.788 and 1.290, respectively)., Conclusions: In patients with suspected glaucoma, an abnormal RNFL classification in the inferior area of the optic disc or an elevated number of abnormal RNFL sectors, as determined by Stratus OCT, were both associated with future VF conversion.

Mammals are serially infected with a variety of microorganisms, including bacteria and parasites. Each infection reprograms the immune system's responses to re-exposure and potentially alters responses to first-time infection by different microorganisms. To examine whether infection with a metazoan parasite modulates host responses to subsequent bacterial infection, mice were infected with the hookworm-like intestinal nematode Nippostrongylus brasiliensis, followed in 2-4 weeks by peritoneal injection of the pathogenic bacterium Klebsiella pneumoniae. Survival from Klebsiella peritonitis two weeks after parasite infection was better in Nippostrongylus-infected animals than in unparasitized mice, with Nippostrongylus-infected mice having fewer peritoneal bacteria, more neutrophils, and higher levels of protective interleukin 6. The improved survival of Nippostrongylus-infected mice depends on IL-4 because the survival benefit is lost in mice lacking IL-4. Because mast cells protect mice from Klebsiella peritonitis, we examined responses in mast cell-deficient Kit(W-sh)/Kit(W-sh) mice, in which parasitosis failed to improve survival from Klebsiella peritonitis. However, adoptive transfer of cultured mast cells to Kit(W-sh)/Kit(W-sh) mice restored survival benefits of parasitosis. These results show that recent infection with Nippostrongylus brasiliensis protects mice from Klebsiella peritonitis by modulating mast cell contributions to host defense, and suggest more generally that parasitosis can yield survival advantages to a bacterially infected host.

The parkinsonian syndromes comprise a highly heterogeneous group of disorders. Although 15 loci are linked to predominantly familial Parkinson's disease (PD), additional PD loci are likely to exist. We recently identified a multigenerational family of Danish and German descent in which five males in three generations presented with a unique syndrome characterized by parkinsonian features and variably penetrant spasticity for which X-linked disease transmission was strongly suggested (XPDS). Autopsy in one individual failed to reveal synucleinopathy; however, there was a significant four-repeat tauopathy in the striatum. Our objective was to identify the locus responsible for this unique parkinsonian disorder. Members of the XPDS family were genotyped for markers spanning the X chromosome. Two-point and multipoint linkage analyses were performed and the candidate region refined by analyzing additional markers. A multipoint LOD(max) score of 2.068 was obtained between markers DXS991 and DXS993. Haplotype examination revealed an approximately 20 cM region bounded by markers DXS8042 and DXS1216 that segregated with disease in all affected males and obligate carrier females and was not carried by unaffected at-risk males. To reduce the possibility of a false-positive linkage result, multiple loci and genes associated with other parkinsonian or spasticity syndromes were excluded. In conclusion, we have identified a unique X-linked parkinsonian syndrome with variable spasticity and four-repeat tau pathology, and defined a novel candidate gene locus spanning approximately 28 Mb from Xp11.2-Xq13.3., ((c) 2010 Movement Disorder Society.)

Background: Treatments for Churg-Strauss syndrome (CSS), a rare eosinophilic vasculitis characterized by asthma, sinusitis, peripheral eosinophilia, pulmonary infiltrates, and tissue infiltration, are limited by toxicity or poor efficacy. Levels of IL-5, a cytokine regulating eosinophils, can be increased in patients with CSS. Mepolizumab, a humanized monoclonal anti-IL-5 antibody, decreases steroid requirements in patients with non-CSS hypereosinophilic syndromes., Objective: The purpose of this study was to assess whether mepolizumab would safely allow corticosteroid tapering in patients with steroid-dependent CSS while decreasing serum markers of disease activity., Methods: This open-label pilot study treated 7 patients with 4 monthly doses of mepolizumab to assess whether it safely decreased CSS disease activity and permitted tapering of systemic corticosteroids., Results: Mepolizumab was safe and well tolerated in patients with CSS. Mepolizumab reduced eosinophil counts and allowed for safe corticosteroid reduction in all 7 subjects. On cessation of mepolizumab, CSS manifestations recurred, necessitating corticosteroid bursts., Conclusion: Mepolizumab is a safe and well-tolerated therapy in patients with CSS, offering clinical benefit by enabling corticosteroid tapering while maintaining clinical stability., (Copyright (c) 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Some studies suggest that patients with asthma who are homozygous for arginine at the 16th amino acid position of the beta2-adrenergic receptor (B16 Arg/Arg) benefit less from treatment with longacting beta2 agonists and inhaled corticosteroids than do those homozygous for glycine (B16 Gly/Gly). We investigated whether there is a genotype-specific response to treatment with a longacting beta2 agonist in combination with inhaled corticosteroid., Methods: In this multicentre, randomised, double-blind, placebo-controlled trial, adult patients with moderate asthma were enrolled in pairs matched for forced expiratory volume in 1 s and ethnic origin, according to whether they had the B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype. Individuals in a matched pair were randomly assigned by computer-generated randomisation sequence to receive inhaled longacting beta2 agonist (salmeterol 50 microg twice a day) or placebo given in a double-blind, crossover design for two 18-week periods. Open-label inhaled corticosteroid (hydrofluoroalkane beclometasone 240 microg twice a day) was given to all participants during the treatment periods. The primary endpoint was morning peak expiratory flow (PEF). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00200967., Findings: After 18 weeks of treatment, mean morning PEF in Arg/Arg participants was 21.4 L/min (95% CI 11.8-31.1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p<0.0001). In Gly/Gly participants, morning PEF was 21.5 L/min (11.0-32.1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p<0.0001). The improvement in PEF did not differ between genotypes (difference [Arg/Arg-Gly/Gly] -0.1, -14.4 to 14.2; p=0.99). In Gly/Gly participants, methacholine PC20 (20% reduction in forced expiratory volume in 1 s; a prespecified secondary outcome) was 2.4 times higher when participants were assigned to salmeterol than when assigned to placebo (p<0.0001). Responsiveness to methacholine did not differ between salmeterol and placebo in Arg/Arg participants (p=0.87). The 2.5 times higher genotype-specific difference in responsiveness to methacholine was significant (1.32 doubling dose difference between genotypes, 0.43-2.21, p=0.0038). Seven Arg/Arg participants (placebo, n=5; salmeterol, n=2) and six Gly/Gly participants (placebo, n=3; salmeterol, n=3) had an asthma exacerbation. Five serious adverse events were reported, one each during the pre-match and run-in phases on open-label inhaled corticosteroid, two during double-blind treatment with salmeterol/inhaled corticosteroid, and one during double-blind treatment with placebo/inhaled corticosteroid. None of the serious events was asthma-related or related to study drugs or procedures., Interpretation: In asthma patients with B16 Arg/Arg and B16 Gly/Gly genotypes, combination treatment with salmeterol and inhaled corticosteroid improved airway function when compared with inhaled corticosteroid therapy alone. These findings suggest that patients should continue to be treated with longacting beta2 agonists plus moderate-dose inhaled corticosteroids irrespective of B16 genotype. Further investigation is needed to establish the importance of the genotype-specific difference in responsiveness to methacholine., Funding: National Institutes of Health.

IL-6 is a biological marker of ventilator-associated lung injury that may contribute to alveolar barrier dysfunction in acute respiratory distress syndrome. To determine whether IL-6 affects alveolar barrier disruption in a model of ventilator-induced lung injury, we examined alveolar barrier albumin flux in wild-type (WT) mice given an IL-6-blocking Ab (IL6AB) and mice deficient in IL-6 (IL6KO). Albumin flux was significantly higher in mice given IL6AB compared with mice given a control Ab. Unexpectedly, albumin flux was similar in WT and IL6KO mice. To examine the mechanisms for these findings, lung neutrophil accumulation (myeloperoxidase activity) was compared, revealing a correlation between lung neutrophil accumulation and albumin flux. IL6AB mice had significantly more lung neutrophils than WT and IL6KO mice, which were similar. Therefore, to determine whether the cellular source of IL-6 influences neutrophil accumulation and alveolar barrier function, chimeric mice were compared. WT/KO chimeras (WT mice with IL6KO hematopoietic cells) showed significantly greater albumin flux and neutrophil accumulation with mechanical ventilation than WT/WT mice. Neutrophil depletion decreased albumin flux in WT and WT/KO mice. IL6KO neutrophils were more adherent in an in vitro assay compared with WT neutrophils. IL-6 from a hematopoietic cell source limits alveolar barrier disruption potentially by reducing neutrophil contact with the endothelium. Modulation of IL-6 signaling in a cell type-specific fashion may be a therapeutic target for patients with acute lung injury.