Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation

Activation of CD4⁺ T cells results in rapid proliferation and differentiation into effector and regulatory subsets. CD4⁺ effector T cell (Teff) (Th1 and Th17) and Treg subsets are metabolically distinct, yet the specific metabolic differences that modify T cell populations are uncertain. Here, we evaluated CD4⁺ T cell populations in murine models and determined that inflammatory Teffs maintain high expression of glycolytic genes and rely on high glycolytic rates, while Tregs are oxidative and require mitochondrial electron transport to proliferate, differentiate, and survive. Metabolic profiling revealed that pyruvate dehydrogenase (PDH) is a key bifurcation point between T cell glycolytic and oxidative metabolism. PDH function is inhibited by PDH kinases (PDHKs). PDHK1 was expressed in Th17 cells, but not Th1 cells, and at low levels in Tregs, and inhibition or knockdown of PDHK1 selectively suppressed Th17 cells and increased Tregs. This alteration in the CD4⁺ T cell populations was mediated in part through ROS, as N-acetyl cysteine (NAC) treatment restored Th17 cell generation. Moreover, inhibition of PDHK1 modulated immunity and protected animals against experimental autoimmune encephalomyelitis, decreasing Th17 cells and increasing Tregs. Together, these data show that CD4⁺ subsets utilize and require distinct metabolic programs that can be targeted to control specific T cell populations in autoimmune and inflammatory diseases.     

Bilateral Improvements in Lower Extremity Function After Unilateral Balance Training in Individuals With Chronic Ankle Instability

Context:

Bilateral improvements in postural control have been reported among individuals with acute lateral ankle sprains and individuals with chronic ankle instability (CAI) when only the unstable ankle is rehabilitated. We do not know if training the stable ankle will improve function on the unstable side.

Objective:

To explore the effects of a unilateral balance-training program on bilateral lower extremity balance and function in individuals with CAI when only the stable limb is trained.

Design:

Cohort study.

Setting:

University clinical research laboratory.

Patients or Other Participants:

A total of 34 volunteers (8 men, 26 women; age = 24.32 ± 4.95 years, height = 167.01 ± 9.45 cm, mass = 77.54 ± 23.76 kg) with CAI were assigned to the rehabilitation (n = 17) or control (n = 17) group. Of those, 27 (13 rehabilitation group, 14 control group) completed the study.

Intervention(s):

Balance training twice weekly for 4 weeks.

Main Outcome Measure(s):

Foot and Ankle Disability Index (FADI), FADI Sport (FADI-S), Star Excursion Balance Test, and Balance Error Scoring System.

Results:

The rehabilitation and control groups differed in changes in FADI-S and Star Excursion Balance Test scores over time. Only the rehabilitation group improved in the FADI-S and in the posteromedial and anterior reaches of the Star Excursion Balance Test. Both groups demonstrated improvements in posterolateral reach; however, the rehabilitation group demonstrated greater improvement than the control group. When the groups were combined, participants reported improvements in FADI and FADI-S scores for the unstable ankle but not the stable ankle.

Conclusions:

Our data suggest training the stable ankle may result in improvements in balance and lower extremity function in the unstable ankle. This further supports the existence of a centrally mediated mechanism in the development of postural-control deficits after injury, as well as improved postural control after rehabilitation.Key Words: overflow, crossover training, rehabilitation

Key Points

• The rehabilitation group performed better over time on the Foot and Ankle Disability Index Sport and the Star Excursion Balance Test (SEBT) in the anterior, posteromedial, and posterolateral directions, but this was not dependent on ankle.
• Training the stable ankle may provide therapeutic benefit to the unstable ankle.
• Performance on the Balance Error Scoring System did not reflect a therapeutic benefit of the neuromuscular-control training program, but the result should be interpreted with caution.
• Clinicians should consider incorporating rehabilitation of the stable ankle in the overall plan for patients who may not be ready to initiate aspects of rehabilitation on the unstable ankle.

Lateral ankle sprain (LAS) is one of the most common injuries that athletes and recreationally active individuals sustain. Researchers have estimated that approximately 23 000 ankle sprains occur each day in the United States, equating to 1 sprain per 10 000 people.¹ As many as 33% to 42% of these injuries result in chronic ankle instability (CAI).^2,3 In the literature, CAI has been defined as the tendency of the ankle to “give way” during normal activity and can occur in the absence of mechanical instability.^4–6 One explanation for this tendency is that damage to the peripheral mechanoreceptors that provide proprioceptive input results in altered efferent modulation. Together, the changes in afferent input and efferent output are recognized as altered neuromuscular control (NMC). When specifically considering the role of NMC in facilitating joint stability, NMC has been defined as “the unconscious activation of dynamic restraints occurring in preparation for and in response to joint motion and loading.”⁷ Ultimately, altered NMC is thought to result in functional ankle instability.^3,4,8 Even after the injury has healed, mechanoreceptors may not function properly, resulting in NMC deficits that can lead to CAI.^3,8In addition to damage at the level of the receptors, changes in central nervous system processing and integration also may contribute to CAI.^9,10 Evidence has suggested that when an injury occurs, this central mechanism for NMC is disrupted.^9–12 Reports of bilateral postural-control deficits after acute LAS have provided further evidence that central pathways are affected by injury.^9,10,13 In addition, researchers^10,14–16 have found bilateral improvements in NMC and postural stability after rehabilitation of acute LAS and CAI. This suggests that NMC is not controlled solely by peripheral mechanoreceptors and that deficits after LAS may be partly due to adaptations in the central pathways. Whereas investigators^10,14–16 have shown a carryover effect after training the involved lower extremity, no one has examined whether training the stable ankle results in improvements to the unstable ankle.Given these reports of bilateral deficits after unilateral injury and improvements in NMC and postural stability in the stable ankle after training only the unstable ankle, it is conceivable that training the stable ankle in individuals with CAI would result in improvements of the unstable ankle. This is meaningful because clinicians may be able to begin neuromuscular retraining earlier and the athlete may be able to return to sport participation better prepared without increasing the time missed. After an acute LAS, many athletes return to sport participation within 15 days¹⁷ despite postural-control deficits being measured up to 21 days after injury⁹ and many reporting pain and functional deficits 6 months later.¹⁷ Researchers¹⁸ also have recommended that NMC training should not begin immediately because of pain and weight-bearing restrictions. Therefore, the amount of time spent restoring NMC before return to sport participation is minimal, likely resulting in athletes returning with residual dysfunction and increased risk for reinjury. By beginning NMC retraining sooner, it is plausible that athletes may return to sport participation with less dysfunction and more prepared for the functional demands of sport. Therefore, the purpose of our study was to explore the effects of a 4-week, unilateral balance-training program on bilateral lower extremity balance and function in individuals with CAI. Our hypothesis was that bilateral improvements would occur after training of the stable ankle.     

Visual attention and the acquisition of information in human crowds

Pedestrian crowds can form the substrate of important socially contagious behaviors, including propagation of visual attention, violence, opinions, and emotional state. However, relating individual to collective behavior is often difficult, and quantitative studies have largely used laboratory experimentation. We present two studies in which we tracked the motion and head direction of 3,325 pedestrians in natural crowds to quantify the extent, influence, and context dependence of socially transmitted visual attention. In our first study, we instructed stimulus groups of confederates within a crowd to gaze up to a single point atop of a building. Analysis of passersby shows that visual attention spreads unevenly in space and that the probability of pedestrians adopting this behavior increases as a function of stimulus group size before saturating for larger groups. We develop a model that predicts that this gaze response will lead to the transfer of visual attention between crowd members, but it is not sufficiently strong to produce a tipping point or critical mass of gaze-following that has previously been predicted for crowd dynamics. A second experiment, in which passersby were presented with two stimulus confederates performing suspicious/irregular activity, supports the predictions of our model. This experiment reveals that visual interactions between pedestrians occur primarily within a 2-m range and that gaze-copying, although relatively weak, can facilitate response to relevant stimuli. Although the above aspects of gaze-following response are reproduced robustly between experimental setups, the overall tendency to respond to a stimulus is dependent on spatial features, social context, and sex of the passerby.     

Erythrocyte Deformability and Oxidative Stress in Inflammatory Bowel Disease

Background  

Oxidative stress and reduced microvascular flow are important factors in the pathogenesis of inflammatory bowel disease (IBD). The increased oxidative stress reduces the eriytrocyte deformability. However, in IBD, there are no studies in the literature which evaluate erythrocyte deformability.