The "Under, Over" Technique for Repair of a Peripheral Bucket-Handle Meniscus Tear With Circumferential Compression Stitches.

The benefits of preserving the meniscus are well-established. Several arthroscopic meniscal repair techniques have been described, such as the inside-out, outside-in, and all-inside. All-inside self-retrieving suture devices can be used to repair vertical, horizontal, and radial tears. However, this technique becomes difficult with large tears, as the jaw of the device cannot reach the peripheral edge of the meniscal tear. We present an all-inside technique using circumferential compression stitches to address large peripheral meniscus tears.

Arthritis flares mediated by tissue-resident memory T cells in the joint.

Rheumatoid arthritis is a systemic autoimmune disease, but disease flares typically affect only a subset of joints, distributed in a distinctive pattern for each patient. Pursuing this intriguing pattern, we show that arthritis recurrence is mediated by long-lived synovial resident memory T cells (TRM). In three murine models, CD8+ cells bearing TRM markers remain in previously inflamed joints during remission. These cells are bona fide TRM, exhibiting a failure to migrate between joints, preferential uptake of fatty acids, and long-term residency. Disease flares result from TRM activation by antigen, leading to CCL5-mediated recruitment of circulating effector cells. Correspondingly, TRM depletion ameliorates recurrence in a site-specific manner. Human rheumatoid arthritis joint tissues contain a comparable CD8+-predominant TRM population, which is most evident in late-stage leukocyte-poor synovium, exhibiting limited T cell receptor diversity and a pro-inflammatory transcriptomic signature. Together, these findings establish synovial TRM as a targetable mediator of disease chronicity in autoimmune arthritis.

IL-1ß-driven osteoclastogenic Tregs accelerate bone erosion in arthritis.

IL-1ß is a proinflammatory mediator with roles in innate and adaptive immunity. Here we show that IL-1ß contributes to autoimmune arthritis by inducing osteoclastogenic capacity in Tregs. Using mice with joint inflammation arising through deficiency of the IL-1 receptor antagonist (Il1rn-/-), we observed that IL-1ß blockade attenuated disease more effectively in early arthritis than in established arthritis, especially with respect to bone erosion. Protection was accompanied by a reduction in synovial CD4+Foxp3+ Tregs that displayed preserved suppressive capacity and aerobic metabolism but aberrant expression of RANKL and a striking capacity to drive RANKL-dependent osteoclast differentiation. Both Il1rn-/- Tregs and wild-type Tregs differentiated with IL-1ß accelerated bone erosion upon adoptive transfer. Human Tregs exhibited analogous differentiation, and corresponding RANKLhiFoxp3+ T cells could be identified in rheumatoid arthritis synovial tissue. Together, these findings identify IL-1ß-induced osteoclastogenic Tregs as a contributor to bone erosion in arthritis.

Evoked Frontal and Parietal Field Potential Signatures of Target Detection and Response Inhibition in Rats Performing an Equiprobable Auditory Go/No-Go Task.

To characterize the rat as a potential model of frontal-parietal auditory processing during sustained attention, target detection, and response inhibition, we recorded field potentials (FPs) at multiple sites in medial-dorsal frontal and posterior parietal cortex simultaneously while rats performed an equiprobable auditory go/no-go discrimination task. Event-related potentials (ERPs) were calculated by averaging tone-triggered FPs across hit, miss, false alarm (FA), and correct rejection (CR) trials separately for each recording session, and five peak amplitudes (termed N1, P2, N2, P3E, and P3L) were extracted from the individual-session ERPs. Comparing peak amplitudes across different trials types indicated a statistically significant amplification of the P2 peak on hit trials that accompanies detection of the target tone prior to the behavioral go response. This result appears analogous to human ERP phenomena during auditory target discrimination. Conversely, the rat P3 responses were not associated with target detection as in the human ERP literature. Likewise, we did not observe the "no-go N2" or "no-go P3" responses reported in the human literature in association with response inhibition, which might reflect differences in task context or a difference in auditory processing between rats and humans. We also present analyses of stimulus-induced spectral power and interarea coherence to characterize oscillatory synchronization which may contribute to ERPs, and discuss possible error-related processing at the N2, P3E, and P3L peaks.

Megakaryocyte emperipolesis mediates membrane transfer from intracytoplasmic neutrophils to platelets.

Bone marrow megakaryocytes engulf neutrophils in a phenomenon termed emperipolesis. We show here that emperipolesis is a dynamic process mediated actively by both lineages, in part through the ß2-integrin/ICAM-1/ezrin pathway. Tethered neutrophils enter in membrane-bound vesicles before penetrating into the megakaryocyte cytoplasm. Intracytoplasmic neutrophils develop membrane contiguity with the demarcation membrane system, thereby transferring membrane to the megakaryocyte and to daughter platelets. This phenomenon occurs in otherwise unmanipulated murine marrow in vivo, resulting in circulating platelets that bear membrane from non-megakaryocytic hematopoietic donors. Transit through megakaryocytes can be completed as rapidly as minutes, after which neutrophils egress intact. Emperipolesis is amplified in models of murine inflammation associated with platelet overproduction, contributing to platelet production in vitro and in vivo. These findings identify emperipolesis as a new cell-in-cell interaction that enables neutrophils and potentially other cells passing through the megakaryocyte cytoplasm to modulate the production and membrane content of platelets.

The metabolic regulator mTORC1 controls terminal myeloid differentiation.

Monocytes are derived from hematopoietic stem cells through a series of intermediate progenitor stages, but the factors that regulate this process are incompletely defined. Using a Ccr2/Cx3cr1 dual-reporter system to model murine monocyte ontogeny, we conducted a small-molecule screen that identified an essential role of mechanistic target of rapamycin complex 1 (mTORC1) in the development of monocytes and other myeloid cells. Confirmatory studies using mice with inducible deletion of the mTORC1 component Raptor demonstrated absence of mature circulating monocytes, as well as disruption in neutrophil and dendritic cell development, reflecting arrest of terminal differentiation at the granulocyte-monocyte progenitor stage. Conversely, excess activation of mTORC1 through deletion of the mTORC1 inhibitor tuberous sclerosis complex 2 promoted spontaneous myeloid cell development and maturation. Inhibitor studies and stage-specific expression profiling identified failure to down-regulate the transcription factor Myc by the mTORC1 target ribosomal S6 kinase 1 (S6K1) as the mechanistic basis for disrupted myelopoiesis. Together, these findings define the mTORC1-S6K1-Myc pathway as a key checkpoint in terminal myeloid development.

Deviance detection by a P3-like response in rat posterior parietal cortex.

To better understand sensory processing in frontal and parietal cortex of the rat, and to further assess the rat as a model of human frontal-parietal processing, we recorded local field potentials (LFPs) from microelectrode arrays implanted in medio-dorsal frontal, and posterior parietal cortex of awake rats as they were presented with a succession of frequent "standard" tones and infrequent "oddball" tones. Extending previous results from surface recordings we found, after controlling for the frequencies of the standard and oddball tones, that rat frontal and parietal-evoked LFPs (eLFPs) exhibit significantly larger N1 (~40 ms latency), P2 (~100 ms), N2 (~160 ms), P3E (~200-240 ms), and P3L (~300-500 ms) amplitudes after an oddball tone. These neural oddball effects could contribute to the automatic allocation of attention to rare stimuli. To determine whether these enhanced responses to rare stimuli could be accounted for in terms of stimulus-specific neural adaptation (SSA), we also recorded during single-tone control sessions involving frequent standard, or infrequent oddball beeps alone. We compared the difference between rare-tone and frequent-tone response amplitudes in the two-tone context (oddball effect) or single-tone context which isolates the contribution of SSA (SSA effect). An analysis of variance (ANOVA) revealed a significant main effect of tone context on rare-tone response enhancements, showing that the rare-tone enhancements were stronger in the two-tone context than the single-tone context. This difference between tone contexts was greatest at the early P3E peak (200-240 ms post-beep) in parietal cortex, suggesting true deviance detection by this evoked response component, which cannot be accounted for in terms of simple models of SSA.