Htr2a-Expressing Cells in the Central Amygdala Control the Hierarchy between Innate and Learned Fear.

Fear is induced by innate and learned mechanisms involving separate pathways. Here, we used an olfactory-mediated innate-fear versus learned-fear paradigm to investigate how these pathways are integrated. Notably, prior presentation of innate-fear stimuli inhibited learned-freezing response, but not vice versa. Whole-brain mapping and pharmacological screening indicated that serotonin-2A receptor (Htr2a)-expressing cells in the central amygdala (CeA) control both innate and learned freezing, but in opposing directions. In vivo fiber photometry analyses in freely moving mice indicated that innate but not learned-fear stimuli suppressed the activity of Htr2a-expressing CeA cells. Artificial inactivation of these cells upregulated innate-freezing response and downregulated learned-freezing response. Thus, Htr2a-expressing CeA cells serve as a hierarchy generator, prioritizing innate fear over learned fear.

Tibiofemoral Relationship 3 Weeks After Anatomic Triple-Bundle Anterior Cruciate Ligament Reconstruction With 10 N of Initial Tension Is Closer to Normal Knee Versus That With 20 N of Initial Tension.

PURPOSE: This study aimed to clarify the effect of initial graft tension on the ensuing tibiofemoral relationship and on 2-year clinical outcomes after anatomic triple-bundle anterior cruciate ligament (ACL) reconstruction. METHODS: A total of 31 patients with primary unilateral ACL rupture (mean age, 25.1 years) were enrolled. Anatomic triple-bundle ACL reconstruction was performed using semitendinosus tendon autografts, and patients were grouped according to the total initial tension at graft fixation: 20 N for 16 patients between January 2012 and December 2012 and 10 N for 15 patients between January 2013 and December 2013. Three-dimensional computed tomography scans were performed preoperatively and at 3 weeks and 6 months postoperatively. The side-to-side difference of the 3-dimensional tibial position relative to the femur was compared at each time point. The side-to-side difference in anterior laxity was sequentially compared preoperatively, immediately after surgery, and at 6 months and 2 years postoperatively. Clinical outcomes at 2 years were likewise compared. RESULTS: One patient in each group was excluded because of secondary ACL injury. At 3 weeks postoperatively, 2.5 ± 1.3 and 1.0 ± 1.3 mm of posterior tibial displacement and 3.8° ± 2.4° and 2.0° ± 1.7° of external rotation were observed in the 20- and 10-N initial tension groups, respectively, with significant differences (P = .006 and .033). At 6 months postoperatively, anterior displacement was 0.1/0.1 mm and external rotation was 0.8°/0.4° in both groups, without any significant differences. The 2-year clinical outcomes were satisfactory, including mean side-to-side difference in anterior knee laxity of 0.5 mm in both groups. CONCLUSION: The tibiofemoral relationship 3 weeks after anatomic triple-bundle ACL reconstruction with 10 N of initial tension is less constrained than that with 20 N. Six-month tibiofemoral relationship and 2-year clinical outcomes are satisfactory in both groups. LEVEL OF EVIDENCE: III, retrospective comparative trial.

Anatomical rectangular tunnel anterior cruciate ligament reconstruction provides excellent clinical outcomes.

PURPOSE: The purpose of this study was to prospectively evaluate the clinical outcomes following anatomical rectangular tunnel anterior cruciate ligament (ACL) reconstruction with a bone-patellar tendon-bone (BTB) graft using an adjustable-length femoral cortical fixation device with enough patients and a high follow-up rate. METHODS: This study included 125 patients who underwent anatomical rectangular tunnel ACL reconstruction with a BTB graft. A BTB TightRope® was used for femoral graft fixation. Clinical evaluations were performed more than 2 years after surgery using the International Knee Documentation Committee (IKDC) Form. Patients interviewed by telephone were only subjectively evaluated. The side-to-side difference in anterior laxity at a manual maximum force was measured using the KT-2000 Arthrometer®. RESULTS: Among the 125 patients, 99 were ultimately included and 26 were lost to follow-up (follow-up rate: 79%). Eight patients had re-tear (re-tear rate: 8%) and six patients had ACL injuries to the contralateral knee. Three patients did not follow our rehabilitation programme. One patient suffered septic arthritis. These 18 patients were considered ineligible for clinical evaluations. Therefore, clinical evaluations were performed in 81 of the 99 patients (64 were available for direct follow-up and 17 were available for a telephone interview). The follow-up period was 30 ± 10 months (range 24-68 months). According to the IKDC subjective assessment, 48 (59%) and 33 (41%) knees were graded as normal and nearly normal, respectively. A loss of extension (3°-5°) was observed in five patients (8%), whereas one patient (2%) exhibited a loss of flexion (3°-5°). The Lachman test was negative in 63 patients (98%). The pivot shift test was negative in 59 patients (92%). The side-to-side difference in KT value was 0.4 ± 0.7 mm (range - 1-4 mm). CONCLUSION: Anatomical rectangular tunnel ACL reconstruction with a BTB graft using an adjustable-length femoral cortical fixation device provided excellent clinical outcomes both subjectively and objectively more than 2 years after surgery, whereas 8 of the 99 patients had re-tear of the graft. The adjustable-length femoral cortical fixation device could be safely used in anatomical rectangular tunnel ACL reconstruction with a BTB graft. LEVEL OF EVIDENCE: III.

The lateral meniscal extrusion after repair with concomitant anterior cruciate ligament reconstruction at a mean follow-up of 3.5 years.

BACKGROUND: A meniscal repair is often performed on radial/flap or longitudinal tears of the lateral meniscus (LM) combined with anterior cruciate ligament reconstruction (ACLR). However, it is unknown if meniscal extrusion changes over time after repair. This study evaluated whether meniscal extrusion of the LM is maintained after repair or progresses with time using magnetic resonance imaging (MRI). METHODS: Among 574 patients who underwent primary anatomic ACLR, 123 patients followed up for more than 2 years were retrospectively analyzed. Forty patients with concomitant radial/flap tears of the LM (group R), 43 with longitudinal LM tears (group L), and 40 with intact LM (group C, matched-control group) were included. Clinical findings (pain, range of motion, swelling, and anterior laxity), lateral joint space on radiograph, and meniscal extrusion on MRI were assessed. Lateral/posterior meniscal extrusions were examined preoperatively, within 3 weeks after surgery, and at the final follow-up, and the absolute values and relative values (the preoperative values as baseline) were assessed respectively. RESULTS: There were no significant differences in the clinical and roentgenographic findings among the groups. No difference was observed in the relative values within 3 weeks after surgery among three groups, although the absolute values were larger in the repaired groups than in group C. At the final follow-up, however, the lateral extrusion in group L had progressed significantly, compared with that in group C (P = 0.033), while no significant difference was detected in the lateral extrusion between groups R and C (P = 0.177). The posterior extrusion in groups R and L had progressed significantly compared with that in group C (P < 0.001). CONCLUSIONS: LM extrusion could not be improved even immediately after meniscal repair, and it progressed laterally and posteriorly for more than 2 years after surgery.

Chronological changes in cross-sectional area of the bone-patellar tendon-bone autograft after anatomic rectangular tunnel ACL reconstruction.

PURPOSE: The purpose of this study was to evaluate the change in cross-sectional area (CSA) of bone-patellar tendon-bone (BTB) autografts up to 5 years after the anatomic rectangular tunnel (ART) anterior cruciate ligament reconstruction (ACLR). The changing pattern in CSA might be a potential indicator of the graft remodeling process. METHODS: Ninety-six (62 males, 34 females, mean age 27.0 years) patients were enrolled in this study with a total of 220 MRI scans after ART BTB ACLR to evaluate the CSA of the ACL autografts. The patients with first time unilateral ACLR that consented to undergo MRI evaluations at postoperative periods were included in this study. Intraoperatively, the CSA of the graft was measured directly using a custom-made area micrometer at the midpoint of the graft. Postoperatively, using an oblique axial slice MRI that was perpendicular to the long axis of the graft, the CSA of the graft was measured with digital radiology viewing program "SYNAPSE" at the midpoint of the graft. The postoperative MRI scans were classified into seven groups according to the period from ACLR to MRI evaluation: Group 0-2 months (m.), Group 3-6 m., Group 7-12 m., Group 1-2 years (y.), Group 2-3 y., Group 3-4 y., and Group 4 y.-. The percent increase of the CSA was calculated by dividing the postoperative CSA by the intraoperative CSA. RESULTS: The postoperative CSA was significantly larger than the intraoperative CSA in each group, with the exception of Group 0-2 m. The mean percent increase of the CSA in Group 0-2 m., 3-6 m., 7-12 m., 1-2 y., 2-3 y., 3-4 y., 4 y.- was 101.8 ± 18.2, 188.9 ± 27.4, 190.9 ± 43.7, 183.3 ± 28.9, 175.2 ± 27.9, 163.9 ± 19.8, 164.5 ± 25.4% respectively. The percent increase in Group 3-6 m., 7-12 m., 1-2 y., 2-3 y., 3-4 y., and 4 y.- was significantly greater than that in Group 0-2 m. CONCLUSIONS: The CSA of the BTB autografts after the ART BTB ACLR increases rapidly by 3-6 months after ACLR, reached a maximum value of 190% at around 1 year, decreases gradually after that, and reaches a plateau at around 3 years. The current study might help clinicians to estimate an individual BTB autograft's remodeling stages when considering returning patients to sports. LEVEL OF EVIDENCE: IV.

tRNA production links nutrient conditions to the onset of sexual differentiation through the TORC1 pathway.

Target of rapamycin (TOR) kinase controls cell growth and metabolism in response to nutrient availability. In the fission yeast Schizosaccharomyces pombe, TOR complex 1 (TORC1) promotes vegetative growth and inhibits sexual differentiation in the presence of ample nutrients. Here, we report the isolation and characterization of mutants with similar phenotypes as TORC1 mutants, in that they initiate sexual differentiation even in nutrient-rich conditions. In most mutants identified, TORC1 activity is downregulated and the mutated genes are involved in tRNA expression or modification. Expression of tRNA precursors decreases when cells undergo sexual differentiation. Furthermore, overexpression of tRNA precursors prevents TORC1 downregulation upon nitrogen starvation and represses the initiation of sexual differentiation. Based on these observations, we propose that tRNA precursors operate in the S. pombe TORC1 pathway to switch growth mode from vegetative to reproductive.

Genetic dissection of pheromone processing reveals main olfactory system-mediated social behaviors in mice.

Most mammals have two major olfactory subsystems: the main olfactory system (MOS) and vomeronasal system (VNS). It is now widely accepted that the range of pheromones that control social behaviors are processed by both the VNS and the MOS. However, the functional contributions of each subsystem in social behavior remain unclear. To genetically dissociate the MOS and VNS functions, we established two conditional knockout mouse lines that led to either loss-of-function in the entire MOS or in the dorsal MOS. Mice with whole-MOS loss-of-function displayed severe defects in active sniffing and poor survival through the neonatal period. In contrast, when loss-of-function was confined to the dorsal MOB, sniffing behavior, pheromone recognition, and VNS activity were maintained. However, defects in a wide spectrum of social behaviors were observed: attraction to female urine and the accompanying ultrasonic vocalizations, chemoinvestigatory preference, aggression, maternal behaviors, and risk-assessment behaviors in response to an alarm pheromone. Functional dissociation of pheromone detection and pheromonal induction of behaviors showed the anterior olfactory nucleus (AON)-regulated social behaviors downstream from the MOS. Lesion analysis and neural activation mapping showed pheromonal activation in multiple amygdaloid and hypothalamic nuclei, important regions for the expression of social behavior, was dependent on MOS and AON functions. Identification of the MOS-AON-mediated pheromone pathway may provide insights into pheromone signaling in animals that do not possess a functional VNS, including humans.

Post-operative deformation and extrusion of the discoid lateral meniscus following a partial meniscectomy with repair.

PURPOSE: The purpose of this study was to investigate the morphology of the discoid lateral meniscus sequentially following a partial meniscectomy with repair using magnetic resonance imaging (MRI). METHODS: Nine patients with a symptomatic discoid lateral meniscus with a peripheral tear were enrolled in this study, and a partial meniscectomy with repair was performed arthroscopically. An MRI examination was performed 2 weeks after surgery (before weight bearing was permitted) and again 6 months after surgery (when sporting activities could resume). The width, height and distance of the discoid lateral meniscus were measured. The distance was defined as the distance between the edges of the discoid lateral meniscus and the tibia. RESULTS: The width of the anterior, middle and posterior segments significantly decreased from 2 weeks to 6 months after surgery. The height of the middle and posterior segments significantly increased from 2 weeks to 6 months after surgery, whereas the height of the anterior segment did not significantly change. The distance of the anterior, middle and posterior segments significantly decreased from 2 weeks to 6 months after surgery. CONCLUSION: The discoid lateral meniscus exhibited deformation and extrusion from 2 weeks to 6 months after a partial meniscectomy with repair. Therefore, the function of load transmission might not be maintained appropriately after surgery. LEVEL OF EVIDENCE: IV.

Cross-sectional area of hamstring tendon autograft after anatomic triple-bundle ACL reconstruction.

PURPOSE: The purpose was to evaluate the cross-sectional area changes in hamstring tendon autografts up to 5 years after the anatomic triple-bundle anterior cruciate ligament (ACL) reconstruction. METHODS: A total of 178 MRI scans from 139 patients (35 males, 104 females, mean age 30.4 years) with the anatomic triple-bundle ACL reconstructions were obtained to evaluate the cross-sectional area of the ACL grafts. They were classified into seven groups according to the period from reconstruction to MRI evaluation: Group -2 months (m.), Group 3-6 m., Group 7-12 m, Group 1-2 years (y.), Group 2-3 y., Group 3-4 y., and Group 4 y.-. Intra-operatively, the cross-sectional area of the graft was measured directly using a custom-made area micrometre. Post-operatively, the cross-sectional area of the grafts' mid-substance was measured with oblique axial MRI slices perpendicular to the long axis of the grafts using a digital radiology viewing program. The percent increase in the cross-sectional area was calculated by dividing the post-operative cross-sectional area by the intra-operative cross-sectional area. RESULTS: The mean percent increase in the cross-sectional area in Groups -2 m., 3-6 m., 7-12 m., 1-2 y., 2-3 y., 3-4 y., and 4 y.- was 105.7 ± 14.0, 134.9 ± 20.0, 137.3 ± 27.8, 129.4 ± 22.2, 124.1 ± 20.4, 117.8 ± 16.9, and 117.1 ± 17.2 %, respectively. The percent increase in Groups 3-6 m., 7-12 m., and 1-2 y. was significantly greater than in Group -2 m., while that in Group 4 y.- was significantly less than in Group 7-12 m. CONCLUSIONS: The cross-sectional area of the hamstring tendon autografts after the anatomic triple-bundle ACL reconstruction increases over time up to 1 year post-operatively, decreases gradually thereafter, and reaches plateau at around 3 years. LEVEL OF EVIDENCE: Retrospective case series, Level IV.

The wiring of Grueneberg ganglion axons is dependent on neuropilin 1.

The Grueneberg ganglion is a specialized olfactory sensor. In mice, its activation induces freezing behavior. The topographical map corresponding to the central projections of its sensory axons is poorly defined, as well as the guidance molecules involved in its establishment. We took a transgenic approach to label exclusively Grueneberg sensory neurons and their axonal projections. We observed that a stereotyped convergence map in a series of coalescent neuropil-rich structures is already present at birth. These structures are part of a peculiar and complex neuronal circuit, composed of a chain of glomeruli organized in a necklace pattern that entirely surrounds the trunk of the olfactory bulb. We found that the necklace chain is composed of two different sets of glomeruli: one exclusively innervated by Grueneberg ganglion neurons, the other by axonal inputs from the main olfactory neuroepithelium. Combining the transgenic Grueneberg reporter mouse with a conditional null genetic approach, we then show that the axonal wiring of Grueneberg neurons is dependent on neuropilin 1 expression. Neuropilin 1-deficient Grueneberg axonal projections lose their strict and characteristic avoidance of vomeronasal glomeruli, glomeruli that are innervated by secondary neurons expressing the repulsive guidance cue and main neuropilin 1 ligand Sema3a. Taken together, our observations represent a first step in the understanding of the circuitry and the coding strategy used by the Grueneberg system.

Bone substitutes and implantation depths for subchondral bone repair in osteochondral defects of porcine knee joints.

PURPOSE: The purpose of this study was to identify the optimal material and implantation method for subchondral bone repair. METHODS: Four osteochondral defects in a femoral groove were created in both knees of 12 pigs, and the total number of defects was 96. Eight defects were left empty (empty group). Beta-tricalcium phosphate (ß-TCP) bone substitutes with 75 and 67 % porosity were implanted in 30 and 29 defects, respectively (ß-TCP75 and ß-TCP67 groups). Hydroxyapatite (HA) bone substitutes with 75 % porosity were filled in 29 defects (HA group). Bone substitutes were implanted at 0, 2, or 4 mm below the subchondral bone plate (SBP). The reparative tissue was assessed using microfocus computed tomography and histology 3 months after implantation. RESULTS: Regardless of the kind of bone substitutes, the defects were filled almost completely after implanting them at the level of the SBP, while the defects remained after implanting them at 2 or 4 mm below the SBP. Reparative tissue of the ß-TCP75 group was similar to the normal cancellous bone, while that of the ß-TCP67 or HA group was not. CONCLUSIONS: Subchondral bone defects were filled almost completely only when bone substitutes were implanted at the level of the SBP. The reparative tissue after implanting the ß-TCP bone substitutes with 75 % porosity was the most similar to the normal cancellous bone. Therefore, implanting the ß-TCP bone substitutes with 75 % porosity at the level of the SBP could be recommended as a treatment method for subchondral bone repair in osteochondral defects. LEVEL OF EVIDENCE: I.

Tibiofemoral relationship following anatomic triple-bundle anterior cruciate ligament reconstruction.

PURPOSE: The purpose of this study was to investigate the tibiofemoral relationship sequentially before and after anatomic triple-bundle (TB) anterior cruciate ligament (ACL) reconstruction in the same patients. METHODS: Nine patients with complete unilateral ACL rupture participated in this study. Anatomic TB ACL reconstruction was performed using autogenous semitendinosus tendon grafts. Computed tomography images were obtained before surgery as well as 3 weeks and 6 months afterwards. During image acquisition, the patient's knees were fully extended in the supine position. Using three-dimensional computer models, anterior-posterior and medial-lateral displacement of the tibia relative to the femur were evaluated for each period, as were internal-external and varus-valgus rotation, followed by calculation of side-to-side differences in parameters. As the control group, 7 healthy volunteers were evaluated. RESULTS: The tibia was located anteriorly by 1.4 ± 0.9 mm and rotated internally by 2.1 ± 1.7° before surgery, while the tibia was located posteriorly by 2.0 ± 1.2 mm and rotated externally by 3.4 ± 3.5° 3 weeks after surgery. Six months after surgery, there was no significant difference between the patient and control groups. CONCLUSIONS: The anteriorly located and internally rotated tibia in ACL-deficient knees was over-constrained (posterior displacement and external rotation) 3 weeks after anatomic TB ACL reconstruction, but returned to the normal position 6 months afterwards. Therefore, anatomic tunnel placement, appropriate initial tension, and moderate rehabilitation can be the key for return to the normal tibiofemoral relationship after ACL reconstruction. LEVEL OF EVIDENCE: Therapeutic study, Level IV.

[Development of meniscus biomaterial].

Meniscus is one of the most important tissues in knee joint from the biomechanical point of view. Meniscus injury is well known to cause osteoarthritis. At moment, there is a limitation of operative repair procedure especially for the meniscus injury with defect. We have been investigating the development of meniscus biomaterials. Meniscus substitute made of atelo-collagen was proved to be one of the candidates of meniscus biomaterial by our experiments using human cell culture, three-dimensional cultured tissue, and animal study.

Prelimbic cortex responds to male ultrasonic vocalizations in the presence of a male pheromone in female mice.

Sensory signals are critical to perform adaptive social behavior. During copulation, male mice emit ultrasonic vocalizations (USVs). Our previous studies have shown that female mice exhibit approach behavior toward sound sources of male USVs and that, after being exposed to a male pheromone, exocrine gland-secreting peptide 1 (ESP1), female mice exhibited a preference toward a particular type of male USVs. These findings suggest that male USVs modulate female courtship behavior. However, it remains unclear which brain regions and what cell types of neurons are involved in neuronal processing of male USVs. To clarify this issue, immediate early gene analysis, behavioral analysis, and neurochemical analysis were performed. The in situ hybridization analysis of c-fos mRNA in multiple brain regions showed that neurons in the prelimbic cortex were responsive to presentation of male USVs in the presence of ESP1. Furthermore, this study found that activity of prelimbic cortex was correlated with the duration of female exploration behavior toward a sound source of the USVs. Finally, by using double immunohistochemistry, the present study showed that the prelimbic neurons responding to the presentation of male USVs were presumably excitatory glutamatergic neurons. These results suggest that the prelimbic cortex may facilitate female courtship behavior in response to male USVs.

Energy-sparing by 2-methyl-2-thiazoline protects heart from ischaemia/reperfusion injury.

AIMS: Cardiac ischaemia/reperfusion (I/R) injury remains a critical issue in the therapeutic management of ischaemic heart failure. Although mild hypothermia has a protective effect on cardiac I/R injury, more rapid and safe methods that can obtain similar results to hypothermia therapy are required. 2-Methyl-2-thiazoline (2MT), an innate fear inducer, causes mild hypothermia resulting in resistance to critical hypoxia in cutaneous or cerebral I/R injury. The aim of this study is to demonstrate the protective effect of systemically administered 2MT on cardiac I/R injury and to elucidate the mechanism underlying this effect. METHODS AND RESULTS: A single subcutaneous injection of 2MT (50 mg/kg) was given prior to reperfusion of the I/R injured 10 week-old male mouse heart and its efficacy was evaluated 24 h after the ligation of the left anterior descending coronary artery. 2MT preserved left ventricular systolic function following I/R injury (ejection fraction, %: control 37.9 ± 6.7, 2MT 54.1 ± 6.4, P < 0.01). 2MT also decreased infarct size (infarct size/ischaemic area at risk, %: control 48.3 ± 12.1, 2MT 25.6 ± 4.2, P < 0.05) and serum cardiac troponin levels (ng/mL: control 8.9 ± 1.1, 2MT 1.9 ± 0.1, P < 0.01) after I/R. Moreover, 2MT reduced the oxidative stress-exposed area within the heart (%: control 25.3 ± 4.7, 2MT 10.8 ± 1.4, P < 0.01). These results were supported by microarray analysis of the mouse hearts. 2MT induced a transient, mild decrease in core body temperature (°C: -2.4 ± 1.4), which gradually recovered over several hours. Metabolome analysis of the mouse hearts suggested that 2MT minimized energy metabolism towards suppressing oxidative stress. Furthermore, 18F-fluorodeoxyglucose-positron emission tomography/computed tomography imaging revealed that 2MT reduced the activity of brown adipose tissue (standardized uptake value: control 24.3 ± 6.4, 2MT 18.4 ± 5.8, P < 0.05). 2MT also inhibited mitochondrial respiration and glycolysis in rat cardiomyoblasts. CONCLUSIONS: We identified the cardioprotective effect of systemically administered 2MT on cardiac I/R injury by sparing energy metabolism with reversible hypothermia. Our results highlight the potential of drug-induced hypothermia therapy as an adjunct to coronary intervention in severe ischaemic heart disease.

Artificial hibernation/life-protective state induced by thiazoline-related innate fear odors.

Innate fear intimately connects to the life preservation in crises, although this relationships is not fully understood. Here, we report that presentation of a supernormal innate fear inducer 2-methyl-2-thiazoline (2MT), but not learned fear stimuli, induced robust systemic hypothermia/hypometabolism and suppressed aerobic metabolism via phosphorylation of pyruvate dehydrogenase, thereby enabling long-term survival in a lethal hypoxic environment. These responses exerted potent therapeutic effects in cutaneous and cerebral ischemia/reperfusion injury models. In contrast to hibernation, 2MT stimulation accelerated glucose uptake in the brain and suppressed oxygen saturation in the blood. Whole-brain mapping and chemogenetic activation revealed that the sensory representation of 2MT orchestrates physiological responses via brain stem Sp5/NST to midbrain PBN pathway. 2MT, as a supernormal stimulus of innate fear, induced exaggerated, latent life-protective effects in mice. If this system is preserved in humans, it may be utilized to give rise to a new field: "sensory medicine."

Outcomes More Than 2 Years After Meniscal Repair for Longitudinal Tears of the Lateral Meniscus Combined With Anterior Cruciate Ligament Reconstruction.

BACKGROUND: Meniscal function after repair of longitudinal tears of the lateral meniscus (LM) with anterior cruciate ligament reconstruction (ACLR) has not been comprehensively investigated. PURPOSE: To evaluate not only the clinical outcomes and radiographic findings of patients who underwent repair of longitudinal tears of the LM combined with ACLR but also the healing status of the repaired meniscus and changes in chondral status with second-look arthroscopy. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Among 548 patients who underwent primary anatomic ACLR at our institution between 2010 and 2017, 39 who had concomitant longitudinal tears of the LM and underwent repair were studied. During follow-up for more than 2 years, all patients were evaluated clinically (pain, range of motion, swelling, and knee instability) and with imaging (plain radiograph and magnetic resonance imaging [MRI]), and compared with a matched control group (based on age, sex, body mass index, and follow-up period) without any concomitant injuries who underwent ACLR. Measurements on MRI were recorded preoperatively, immediately after surgery, and at final follow-up, and the change in the values over time was assessed. Of the 39 patients in each group, 24 were assessed by second-look arthroscopy with hardware removal 2 years postoperatively. RESULTS: The mean follow-up times of the study and control group were at a mean of 42.4 and 45.4 months, respectively. There were no significant differences in clinical findings, lateral joint space narrowing on radiographs, and chondral status at the lateral compartment between groups, whereas lateral and posterior meniscal extrusion on MRI progressed significantly in the study group (0.43 ± 1.0 mm vs -0.29 ± 1.1 mm, P = .003; 1.9 ± 1.9 mm vs 0.14 ± 1.1 mm, P < .0001, respectively). Second-look arthroscopy revealed complete healing in 12 patients (50%), partial healing in 9 (37.5%), and failure in 3 (12.5%) in the study group, and no new tear in the control group. CONCLUSION: The clinical and imaging outcomes after repair of longitudinal tears of the LM combined with anatomic ACLR were successful and comparable with those after isolated ACLR without any other injuries at 42 months postoperatively, although meniscal extrusion showed progression on coronal/sagittal MRI. Based on the MRI findings and the result that only half of patients achieved complete healing, meniscal function could not be fully restored even after repair. Although degenerative changes were not apparent, longer-term follow-up is needed.

Thiazoline-related innate fear stimuli orchestrate hypothermia and anti-hypoxia via sensory TRPA1 activation.

Thiazoline-related innate fear-eliciting compounds (tFOs) orchestrate hypothermia, hypometabolism, and anti-hypoxia, which enable survival in lethal hypoxic conditions. Here, we show that most of these effects are severely attenuated in transient receptor potential ankyrin 1 (Trpa1) knockout mice. TFO-induced hypothermia involves the Trpa1-mediated trigeminal/vagal pathways and non-Trpa1 olfactory pathway. TFOs activate Trpa1-positive sensory pathways projecting from trigeminal and vagal ganglia to the spinal trigeminal nucleus (Sp5) and nucleus of the solitary tract (NTS), and their artificial activation induces hypothermia. TFO presentation activates the NTS-Parabrachial nucleus pathway to induce hypothermia and hypometabolism; this activation was suppressed in Trpa1 knockout mice. TRPA1 activation is insufficient to trigger tFO-mediated anti-hypoxic effects; Sp5/NTS activation is also necessary. Accordingly, we find a novel molecule that enables mice to survive in a lethal hypoxic condition ten times longer than known tFOs. Combinations of appropriate tFOs and TRPA1 command intrinsic physiological responses relevant to survival fate.

Loss of the TOR kinase Tor2 mimics nitrogen starvation and activates the sexual development pathway in fission yeast.

Fission yeast has two TOR (target of rapamycin) kinases, namely Tor1 and Tor2. Tor1 is required for survival under stressed conditions, proper G(1) arrest, and sexual development. In contrast, Tor2 is essential for growth. To analyze the functions of Tor2, we constructed two temperature-sensitive tor2 mutants. Interestingly, at the restrictive temperature, these mutants mimicked nitrogen starvation by arresting the cell cycle in G(1) phase and initiating sexual development. Microarray analysis indicated that expression of nitrogen starvation-responsive genes was induced extensively when Tor2 function was suppressed, suggesting that Tor2 normally mediates a signal from the nitrogen source. As with mammalian and budding yeast TOR, we find that fission yeast TOR also forms multiprotein complexes analogous to TORC1 and TORC2. The raptor homologue, Mip1, likely forms a complex predominantly with Tor2, producing TORC1. The rictor/Avo3 homologue, Ste20, and the Avo1 homologue, Sin1, appear to form TORC2 mainly with Tor1 but may also bind Tor2. The Lst8 homologue, Wat1, binds to both Tor1 and Tor2. Our analysis shows, with respect to promotion of G(1) arrest and sexual development, that the loss of Tor1 (TORC2) and the loss of Tor2 (TORC1) exhibit opposite effects. This highlights an intriguing functional relationship among TOR kinase complexes in the fission yeast Schizosaccharomyces pombe.