Progressive cognitive impairment after recovery from neuroinvasive and non-neuroinvasive Listeria monocytogenes infection.

Background: Neuro-cognitive impairment is a deleterious complication of bacterial infections that is difficult to treat or prevent. Listeria monocytogenes (Lm) is a neuroinvasive bacterial pathogen and commonly used model organism for studying immune responses to infection. Antibiotic-treated mice that survive systemic Lm infection have increased numbers of CD8+ and CD4+ T-lymphocytes in the brain that include tissue resident memory (TRM) T cells, but post-infectious cognitive decline has not been demonstrated. We hypothesized that Lm infection would trigger cognitive decline in accord with increased numbers of recruited leukocytes. Methods: Male C57BL/6J mice (age 8 wks) were injected with neuroinvasive Lm 10403s, non-neuroinvasive Δhly mutants, or sterile saline. All mice received antibiotics 2-16d post-injection (p.i.) and underwent cognitive testing 1 month (mo) or 4 mo p.i. using the Noldus PhenoTyper with Cognition Wall, a food reward-based discrimination procedure using automated home cage based observation and monitoring. After cognitive testing, brain leukocytes were quantified by flow cytometry. Results: Changes suggesting cognitive decline were observed 1 mo p.i. in both groups of infected mice compared with uninfected controls, but were more widespread and significantly worse 4 mo p.i. and most notably after Lm 10403s. Impairments were observed in learning, extinction of prior learning and distance moved. Infection with Lm 10403s, but not Δhly Lm, significantly increased numbers of CD8+ and CD4+ T-lymphocytes, including populations expressing CD69 and TRM cells, 1 mo p.i. Numbers of CD8+, CD69+CD8+ T-lymphocytes and CD8+ TRM remained elevated at 4 mo p.i. but numbers of CD4+ cells returned to homeostatic levels. Higher numbers of brain CD8+ T-lymphocytes showed the strongest correlations with reduced cognitive performance. Conclusions: Systemic infection by neuroinvasive as well as non-neuroinvasive Lm triggers a progressive decline in cognitive impairment. Notably, the deficits are more profound after neuroinvasive infection that triggers long-term retention of CD8+ T-lymphocytes in the brain, than after non-neuroinvasive infection, which does not lead to retained cells in the brain. These results support the conclusion that systemic infections, particularly those that lead to brain leukocytosis trigger a progressive decline in cognitive function and implicate CD8+ T-lymphocytes, including CD8+TRM in the etiology of this impairment.

Postless Hip Distraction Systems Decrease the Amount of Traction Force Needed to Obtain Adequate Hip Distraction Versus a Conventional Post Hip Distractor.

PURPOSE: To directly compare hip distraction distance and traction force data for hip arthroscopy performed using a post-basedsystem versus a postless system. METHODS: Adult patients undergoing primary hip arthroscopy for femoroacetabular impingement were prospectively enrolled. Before March 26, 2019, arthroscopy was performed using a post-based system. After this date, the senior author converted to using a postless system. Intraoperative traction force and fluoroscopic distraction distance were measured to calculate hip stiffness coefficients at holding traction (k-hold) and maximal traction (k-max). We used multivariable regression analysis to determine whether postless arthroscopy was predictive of lower stiffness coefficients when controlling for other relevant patient-specific factors. RESULTS: Hip arthroscopy was performed with a post-based system in 105 patients and with a postless system in 51. Mean holding traction force (67.5 ± 14.0 kilograms-force [kgf] vs 55.8 ± 15.3 kgf) and mean maximum traction force (96.0 ± 16.6 kgf vs 69.9 ± 14.1 kgf) were significantly lower in the postless group. On multivariable analysis, postless traction was an independent predictor of decreased k-hold (ß = -31.4; 95% confidence interval, -61.2 to -1.6) and decreased k-max (ß = -90.4; 95% confidence interval, -127.8 to -53.1). Male sex, Beighton score of 0, and poor hamstring flexibility were also predictors of increased k-hold and k-max in the multivariable model. CONCLUSIONS: Postless traction systems decrease the amount of traction force required for adequate hip distraction for both maximal and holding traction forces when compared with post-based systems. Postless traction systems may help further reduce distraction-type neurologic injuries and pain after hip arthroscopy by lowering the traction force required to safely distract the hip. LEVEL OF EVIDENCE: Level III, prospective cohort-historical control comparative study.

A New Case and Comprehensive Review of the Ophthalmic Manifestations of 172 Individuals With Branchio-Oculo-Facial Syndrome.

PURPOSE: To review the literature on branchio-oculo-facial syndrome and describe a new case. METHODS: A girl presented with a de novo pathogenic mutation in the TFAP2A gene consistent with branchio-oculo-facial syndrome. A systematic review was also performed to characterize the eye manifestations associated with the syndrome. RESULTS: A total of 172 total patients were identified from the literature. Among these, 102 patients received molecular confirmation. The most common pathogenic variants reported were p.R255G, p.A256V, p.R254W, and p.G251E. Common eye abnormalities associated with the syndrome in total combined cases (represents individuals with a clinical diagnosis only of branchio-oculo-facial syndrome plus those who additionally had molecular confirmation of the syndrome from genetic testing) were nasolacrimal duct stenosis (n = 98, 57%), coloboma (n = 76, 46%), anophthalmia/microphthalmia (n = 64, 37%), and cataracts (n = 27, 16%). CONCLUSIONS: This analysis provides a comprehensive review of genetic variants and ophthalmic findings to characterize the most common eye manifestations associated with branchio-oculo-facial syndrome. The report provides incentive to further investigate TFAP2A variants and identify genotype-phenotype correlations. [J Pediatr Ophthalmol Strabismus. 2023;60(4):295-301.].

Reactive balance assessments complement clinical baseline concussion assessments in collegiate athletes.

CONTEXT: Current clinical concussion evaluations assess balance deficits using static or dynamic balance tasks while largely ignoring reactive balance. Including a reactive balance assessment in current evaluations might provide a more comprehensive concussion evaluation. OBJECTIVE: The purpose of this study was to determine if redundancy exists within current clinical baseline assessments of concussion and whether reactive balance adds unique information to these evaluations. DESIGN: Cross Sectional Study. SETTING: Clinical Assessment. PATIENTS OR OTHER PARTICIPANTS: Two cohorts of data were collected at the beginning of the athletic season from healthy NCAA Division I athletes. Within the first cohort (n = 191), correlation analyses with clinical scores and inertial measurements were run between the ImPACT (Immediate Post-Concussion Assessment and Cognitive Tool), the BESS (Balance Error Scoring System), the modified Push and Release (mP&R), and instrumented mP&R (I-mP&R) to determine the strength of a relationship between these concussion tests. Within the second cohort (n = 88), correlation analyses were run between the BESS, the mP&R, Timed Tandem Gait, Walking with eyes closed, and clinical reaction time to determine the strength of the relationship between these concussion evaluation tests. MAIN OUTCOME MEASURES: ImPACT cognitive indices, BESS and mP&R clinical score and instrumented measures (BESS sway; I-mP&R time to stability, latency, and step length), TTG and Walking time to completion, and clinical reaction time. RESULTS: The strongest inter-instrument correlation value was r= 0.347, which was considered a weak correlation, between clinical reaction time and single task time to stability from the I-mP&R. The I-mP&R and mP&R clinical scores were weakly associated with the other assessments. CONCLUSION: The weak correlations between inter-assessment variables indicates that there is little redundancy within the current clinical evaluations. Furthermore, reactive balance represents a unique domain of function that may improve the comprehensiveness of clinical assessments.

Systemic Listeria monocytogenes infection in aged mice induces long-term neuroinflammation: the role of miR-155.

BACKGROUND: Understanding mechanisms of pathologic neuroinflammation is essential for improving outcomes after central nervous system infections. Brain tissue-resident memory T cells (bTRM) are recruited during central nervous system infection and promote pathogen control as well as noxious inflammation. Our prior studies in young mice showed optimal recruitment of CD8+ bTRM during neuroinvasive Listeria monocytogenes (Lm) infection required miR-155, and was significantly inhibited by anti-miR-155 oligonucleotides. Since Lm is an important pathogen in the elderly, we hypothesized anti-miR-155 would also inhibit accumulation of CD8+ bTRM in aged mice infected with Lm. METHODS: Young (2 mo) and aged (> 18 mo) male C57BL/6 mice were infected intra-peritoneally with wild-type Lm, or avirulent Lm mutants lacking the genes required for intracellular motility (ΔactA) or phagosomal escape (Δhly), then were given antibiotics. Brain leukocytes and their intracellular cytokine production were quantified by flow cytometry >28d post-infection (p.i.). The role of miR-155 was tested by injecting mice with anti-miR-155 or control oligonucleotides along with antibiotics. RESULTS: Aged mice had significantly more homeostatic CD8+ bTRM than did young mice, which did not increase after infection with wild-type Lm despite 50% mortality, whereas young mice suffered no mortality after a larger inoculum. For direct comparison of post-infectious neuroinflammation after the same inoculum, young and aged mice were infected with 107 CFU ΔactA Lm. This mutant caused no mortality and significantly increased CD8+ bTRM 28d p.i. in both groups, whereas bone marrow-derived myeloid cells, particularly neutrophils, increased only in aged mice. Notably, anti-miR-155 reduced accumulation of brain myeloid cells in aged mice after infection, whereas CD8+ bTRM were unaffected. CONCLUSIONS: Systemic infection with Lm ΔactA is a novel model for studying infection-induced brain inflammation in aged mice without excessive mortality. CD8+ bTRM increase in both young and aged mice after infection, whereas only in aged mice bone marrow-derived myeloid cells increase long-term. In aged mice, anti-miR-155 inhibits brain accumulation of myeloid cells, but not CD8+ bTRM. These results suggest young and aged mice differ in manifestations and mechanisms of infection-induced neuroinflammation and give insight for developing therapies to ameliorate brain inflammation following severe infection in the elderly.

Neurocognitive aging data release with behavioral, structural and multi-echo functional MRI measures.

Central to understanding human behavior is a comprehensive mapping of brain-behavior relations within the context of lifespan development. Reproducible discoveries depend upon well-powered samples of reliable data. We provide to the scientific community two, 10-minute, multi-echo functional MRI (ME-fMRI) runs, and structural MRI (T1-MPRAGE), from 181 healthy younger (ages 18-34 y) and 120 older adults (ages 60-89 y). T2-FLAIR MRIs and behavioral assessments are available in a majority subset of over 250 participants. Behavioral assessments include fluid and crystallized cognition, self-reported measures of personality, and socioemotional functioning. Initial quality control and validation of these data is provided. This dataset will be of value to scientists interested in BOLD signal specifically isolated from ME-fMRI, individual differences in brain-behavioral associations, and cross-sectional aging effects in healthy adults. Demographic and behavioral data are available within the Open Science Framework project "Goal-Directed Cognition in Older and Younger Adults" ( http://osf.io/yhzxe/ ), which will be augmented over time; neuroimaging data are available on OpenNeuro ( https://openneuro.org/datasets/ds003592 ).

Age differences in the functional architecture of the human brain.

The intrinsic functional organization of the brain changes into older adulthood. Age differences are observed at multiple spatial scales, from global reductions in modularity and segregation of distributed brain systems, to network-specific patterns of dedifferentiation. Whether dedifferentiation reflects an inevitable, global shift in brain function with age, circumscribed, experience-dependent changes, or both, is uncertain. We employed a multimethod strategy to interrogate dedifferentiation at multiple spatial scales. Multi-echo (ME) resting-state fMRI was collected in younger (n = 181) and older (n = 120) healthy adults. Cortical parcellation sensitive to individual variation was implemented for precision functional mapping of each participant while preserving group-level parcel and network labels. ME-fMRI processing and gradient mapping identified global and macroscale network differences. Multivariate functional connectivity methods tested for microscale, edge-level differences. Older adults had lower BOLD signal dimensionality, consistent with global network dedifferentiation. Gradients were largely age-invariant. Edge-level analyses revealed discrete, network-specific dedifferentiation patterns in older adults. Visual and somatosensory regions were more integrated within the functional connectome; default and frontoparietal control network regions showed greater connectivity; and the dorsal attention network was more integrated with heteromodal regions. These findings highlight the importance of multiscale, multimethod approaches to characterize the architecture of functional brain aging.

Reactive Balance Responses After Mild Traumatic Brain Injury: A Scoping Review.

OBJECTIVE: Balance testing after concussion or mild traumatic brain injury (mTBI) can be useful in determining acute and chronic neuromuscular deficits that are unapparent from symptom scores or cognitive testing alone. Current assessments of balance do not comprehensively evaluate all 3 classes of balance: maintaining a posture; voluntary movement; and reactive postural response. Despite the utility of reactive postural responses in predicting fall risk in other balance-impaired populations, the effect of mTBI on reactive postural responses remains unclear. This review sought to (1) examine the extent and range of available research on reactive postural responses in people post-mTBI and (2) determine whether reactive postural responses (balance recovery) are affected by mTBI. DESIGN: Scoping review. METHODS: Studies were identified using MEDLINE, EMBASE, CINAHL, Cochrane Library, Dissertations and Theses Global, PsycINFO, SportDiscus, and Web of Science. Inclusion criteria were injury classified as mTBI with no confounding central or peripheral nervous system dysfunction beyond those stemming from the mTBI, quantitative measure of reactive postural response, and a discrete, externally driven perturbation was used to test reactive postural response. RESULTS: A total of 4747 publications were identified, and a total of 3 studies (5 publications) were included in the review. CONCLUSION: The limited number of studies available on this topic highlights the lack of investigation on reactive postural responses after mTBI. This review provides a new direction for balance assessments after mTBI and recommends incorporating all 3 classes of postural control in future research.

Interadministrator Reliability of a Modified Instrumented Push and Release Test of Reactive Balance.

CONTEXT: Traditional assessments of reactive balance require sophisticated instrumentation to ensure objective, highly repeatable paradigms. This instrumentation is clinically impractical. The Push and Release test (P&R) is a well-validated clinical test that examines reactive balance, and the application of wearable inertial measurement units (IMU) enables sensitive and objective assessment of this clinically feasible test. The P&R relies on administrator experience and may be susceptible to interadministration reliability concerns. The purpose of this study was to evaluate the interadministrator reliability of objective outcomes from an instrumented, modified version of the P&R test. DESIGN: Crossover interadministrator design. METHODS: Twenty healthy adults (20-35 y) completed the P&R in 4 directions with 2 different administrators. Measures quantified using IMUs included step latency, step length, and time to stability. Lean angle (LA) at release was used as a measure of administration consistency. The intraclass correlation coefficient (ICC) estimate was used to assess interadministrator reliability in each direction. To determine consistency of LA within and across administrators, we calculated the SDs for each rater by direction and the interadministrator reliability of LA using ICC. RESULTS: Across individual directions, the ICC for agreement between raters ranged from .16 to .39 for step latency, from .52 to .62 for time to stability, and from .48 to .84 for step length. Summary metrics across all 4 directions produced higher ICC values. There was poor to moderate consistency in administration based on LA, but LA did not significantly affect any of the outcomes. CONCLUSION: The modified P&R yields moderate interadministrator reliability and high validity. Summary metrics over all 4 directions (the maximum step latency, the median time to stability, and the median step length) are likely more reliable than direction-specific scores. Variations in body size should also be considered when comparing populations.

Endothelial Dysfunction and Impaired Neurovascular Coupling Responses Precede Cognitive Impairment in a Mouse Model of Geriatric Sepsis.

Sepsis is a life-threatening condition, the incidence of which is significantly increased in elderly patients. One of the long-lasting effects of sepsis is cognitive impairment defined as a new deficit or exacerbation of preexisting deficits in global cognition or executive function. Normal brain function is dependent on moment-to-moment adjustment of cerebral blood flow to match the increased demands of active brain regions. This homeostatic mechanism, termed neurovascular coupling (NVC, also known as functional hyperemia), is critically dependent on the production of vasodilator NO by microvascular endothelial cells in response to mediators released from activated astrocytes. The goal of this study was to test the hypothesis that sepsis in aging leads to impairment of NVC responses early after treatment and that this neurovascular dysfunction associates with impairments in cognitive performance and vascular endothelial dysfunction. To test this hypothesis, we used a commonly studied bacterial pathogen, Listeria monocytogenes, to induce sepsis in experimental animals (males, 24 months of age) and subjected experimental animals to a standard clinical protocol of 3 doses of ampicillin i.p. and 14 days of amoxicillin added to the drinking water. NVC responses, endothelial function and cognitive performance were measured in septic and age-matched control groups within 14 days after the final antibiotic treatment. Our data demonstrate that sepsis in aging significantly impairs NVC responses measured in somatosensory cortex during whisker stimulation, significantly impairs endothelial function in isolated and pressure cannulated aorta rings in response to acetylcholine stimulation. No significant impairment of cognitive function in post-sepsis aged animals has been observed when measured using the PhenoTyper homecage based system. Our findings suggest that sepsis-associated endothelial dysfunction and impairment of NVC responses may contribute to long-term cognitive deficits in older sepsis survivors.

Reactive Postural Responses After Mild Traumatic Brain Injury and Their Association With Musculoskeletal Injury Risk in Collegiate Athletes: A Study Protocol.

Background: Deficits in neuromuscular control are widely reported after mild traumatic brain injury (mTBI). These deficits are speculated to contribute to the increased rate of musculoskeletal injuries after mTBI. However, a concrete mechanistic connection between post-mTBI deficits and musculoskeletal injuries has yet to be established. While impairments in some domains of balance control have been linked to musculoskeletal injuries, reactive balance control has received little attention in the mTBI literature, despite the inherent demand of balance recovery in athletics. Our central hypothesis is that the high rate of musculoskeletal injuries after mTBI is in part due to impaired reactive balance control necessary for balance recovery. The purpose of this study is to (1) characterize reactive postural responses to recover balance in athletes with recent mTBI compared to healthy control subjects, (2) determine the extent to which reactive postural responses remain impaired in athletes with recent mTBI who have been cleared to return to play, and (3) determine the relationship between reactive postural responses and acute lower extremity musculoskeletal injuries in a general sample of healthy collegiate athletes. Methods: This two-phase study will take place at the University of Utah in coordination with the University of Utah Athletics Department. Phase 1 will evaluate student-athletes who have sustained mTBI and teammate-matched controls who meet all the inclusion criteria. The participants will be assessed at multiple time points along the return-to-play progress of the athlete with mTBI. The primary outcome will be measures of reactive postural response derived from wearable sensors during the Push and Release (P&R) test. In phase 2, student-athletes will undergo a baseline assessment of postural responses. Acute lower extremity musculoskeletal injuries for each participant will be prospectively tracked for 1 year from the date of first team activity. The primary outcomes will be the measures of reactive postural responses and the time from first team activity to lower extremity injury. Discussion: Results from this study will further our understanding of changes in balance control, across all domains, after mTBI and identify the extent to which postural responses can be used to assess injury risk in collegiate athletes.

Anionic phospholipid expression as a molecular target in Listeria monocytogenes and Escherichia coli.

This study validates bacterial anionic phospholipids (APs) as a putative molecular target in a novel antibiotic treatment against the Gram-positive bacterium Listeria monocytogenes and the Gram-negative bacterium Escherichia coli. Bacterial AP expression was targeted with its associated protein-ligand partner, annexin A5 (ANXA5). This protein was functionalised with the covalent addition of the antibiotic ampicillin (AMP) and separately with the antibiotic moxifloxacin (MOX). Functionalised ANXA5 serves as a delivery vehicle, directing the antibiotic to bacterial AP expression. The results presented here suggest that this ANXA5-AMP bioconjugate participates in a positive feedback loop where APs, the target of the delivery vehicle ANXA5, are upregulated by the chemotherapeutic payload of the bioconjugate. Importantly, the ANXA5 delivery vehicle is non-toxic to bacterial cells by itself and neither is the ANXA5-antibiotic bioconjugate toxic to human vascular endothelial cells. As measured by the IC50, conjugation to ANXA5 resulted in increasing the antibiotic activity of AMP against L. monocytogenes and E. coli by more than 4 and 3 orders of magnitude, respectively, compared with free AMP, whilst the activity of MOX against L. monocytogenes is increased by 4 orders of magnitude. Given the conservation of AP expression in pathologies such as oncogenesis and other bacterial/viral/parasitic infections, we hypothesise that a therapeutic modality targeting AP expression may be a viable chemotherapeutic strategy in many infectious diseases.

Neuroinvasive Listeria monocytogenes infection triggers accumulation of brain CD8+ tissue-resident memory T cells in a miR-155-dependent fashion.

BACKGROUND: Brain inflammation is a key cause of cognitive decline after central nervous system (CNS) infections. A thorough understanding of immune responses to CNS infection is essential for developing anti-inflammatory interventions that improve outcomes. Tissue-resident memory T cells (TRM) are non-recirculating memory T cells that provide surveillance of previously infected tissues. However, in addition to protecting the brain against reinfection, brain TRM can contribute to post-infectious neuroinflammation. We hypothesized that accumulation of CD8+ TRM in the brain could be reduced by inhibiting microRNA (miR)-155, a microRNA that influences development of cytotoxic CD8+ T lymphocytes during infection. METHODS: C57BL/6J mice were infected by intraperitoneal injection with a lethal inoculum of Listeria monocytogenes (Lm) then treated with antibiotics. Flow cytometry was used to quantify specific populations of brain leukocytes 28-29 days (d) post-infection (p.i.). To test the degree to which miR-155 altered leukocyte influxes into the brain, infected mice were injected with a miR-155 inhibitor or locked nucleic acid (LNA) scramble control 2d, 4d, 6d, and 8d p.i. along with antibiotic treatment. Bacterial loads in spleen and liver and body weights were measured up to 7d p.i. Brain leukocytes were analyzed 14d and 28d p.i. Confirmatory studies were performed in mutated mice lacking miR-155 (miR-155-/-) RESULTS: Lm infection significantly increased the numbers of brain CD3+CD8+ lymphocytes at 28d p.i. These cells were extravascular, and displayed markers characteristic of TRM, with the predominant phenotype of CD44+CD62L-CD69+CX3CR1-. Further analysis showed that > 75% of brain TRM also expressed CD49a, PD-1, Ly6C, CD103, and CD127. Mice injected with miR-155 inhibitor lost less weight through 7d p.i. than did control mice, whereas bacterial loads in brain, liver, and spleen were not different from controls. By 28d p.i., the numbers of brain CD8+ TRM cells were significantly decreased in mice treated with the inhibitor compared with controls. Similarly, miR-155-/- mice showed significantly reduced numbers of brain CD8+ TRM cells by 28d p.i. CONCLUSIONS: Brain CD8+ TRM populations are established during neuroinvasive Lm infection. Accumulation of brain CD8+ TRM cells is reduced by blocking miR-155 and in miR-155-/- mice, indicating that this molecule has a critical role in development of these specialized cells. Administering anti-miR-155 during infection could provide a novel avenue for reducing post-infectious neuroinflammation.

Neuroinvasive Listeria monocytogenes Infection Triggers IFN-Activation of Microglia and Upregulates Microglial miR-155.

MicroRNA (miR) miR-155 modulates microglial activation and polarization, but its role in activation of microglia during bacterial brain infection is unclear. We studied miR-155 expression in brains of C57BL/6 (B6.WT) mice infected i.p. with the neuro-invasive bacterial pathogen Listeria monocytogenes (L. monocytogenes). Infected mice were treated with ampicillin starting 2 days (d) post-infection (p.i.) and analyzed 3d, 7d, and 14d p.i. Virulent L. monocytogenes strains EGD and 10403s upregulated miR-155 in whole brain 7 d p.i. whereas infection with avirulent, non-neurotropic Δhly or ΔactA L. monocytogenes mutants did not. Similarly, infection with virulent but not mutated bacteria upregulated IFN-γ mRNA in the brain at 7 d p.i. Upregulation of miR-155 in microglia was confirmed by qPCR of flow cytometry-sorted CD45intCD11bpos brain cells. Subsequently, brain leukocyte influxes and gene expression in sorted microglia were compared in L. monocytogenes-infected B6.WT and B6.Cg-Mir155tm1.1Rsky/J (B6.miR-155-/-) mice. Brain influxes of Ly-6Chigh monocytes and upregulation of IFN-related genes in microglia were similar to B6.WT mice at 3 d p.i. In contrast, by d 7 p.i. expressions of microglial IFN-related genes, including markers of M1 polarization, were significantly lower in B6.miR-155-/- mice and by 14 d p.i., influxes of activated T-lymphocytes were markedly reduced. Notably, CD45highCD11bpos brain cells from B6.miR-155-/- mice isolated at 7 d p.i. expressed 2-fold fewer IFN-γ transcripts than did cells from B6.WT mice suggesting reduced IFN-γ stimulation contributed to dampened gene expression in B6.miR-155-/- microglia. Lastly, in vitro stimulation of 7 d p.i. brain cells with heat-killed L. monocytogenes induced greater production of TNF in B6.miR-155-/- microglia than in B6.WT microglia. Thus, miR-155 affects brain inflammation by multiple mechanisms during neuroinvasive L. monocytogenes infection. Peripheral miR-155 promotes brain inflammation through its required role in optimal development of IFN-γ-secreting lymphocytes that enter the brain and activate microglia. Microglial miR-155 promotes M1 polarization, and also inhibits inflammatory responses to stimulation by heat-killed L. monocytogenes, perhaps by targeting Tab2.

Critical Importance of Low-Dose Tissue Plasminogen Activator Policy for Treating Intraoperative Pulmonary Thromboembolism During Liver Transplantation.

Tissue plasminogen activator (tPA) has been reported to treat intraoperative pulmonary thromboembolism (PTE) during liver transplantation (LT). However, tPA administration is often delayed due to fear of uncontrolled bleeding and storage in a refrigerator outside of operating rooms. Various dosages of tPA were used. We hypothesize that a policy of tPA storage and low dosage use improves patient outcomes. At a transplantation center, a multidisciplinary committee has implemented a tPA policy since April 2014, which includes the following: (1) timely administering of low-dose tPA (0.5-4 mg) for intraoperative PTE; (2) keeping 2 vials of tPA (2 mg/vial) in the operating room at room temperature; and (3) transferring unused tPA vials to the cardiology catheterization laboratory for next-day use. A prospective observational study was conducted to record the incidence and outcome of PTE during LTs. Over the next 19 months, 99 adult deceased donor LTs were performed with 1 (1.0%) intraoperative PTE. A 45-year-old woman with hepatitis C developed PTE within 5 minutes after graft reperfusion. A 2-mg tPA was immediately administered via a central venous line with hemodynamic improvement and clot lysis. Thromboelastography was normalized in 90 minutes. Five LT cases developing intraoperative PTE have been reported to receive "standard" dosages of tPA (20-110 mg) or urokinase (4400 IU/kg), which were administered more than 20 minutes after the diagnosis of PTE. One intraoperative death and one later mortality were noted with intracranial hemorrhages/infarction of 3 cases. The multidisciplinary low-dose tPA policy for PTE was suggested to be effective.

Financial Exploitation Is Associated With Structural and Functional Brain Differences in Healthy Older Adults.

BACKGROUND: Age-related brain changes leading to altered socioemotional functioning may increase vulnerability to financial exploitation. If confirmed, this would suggest a novel mechanism leading to heightened financial exploitation risk in older adults. Development of predictive neural markers could facilitate increased vigilance and prevention. In this preliminary study, we sought to identify structural and functional brain differences associated with financial exploitation in older adults. METHODS: Financially exploited older adults (n = 13, 7 female) and a matched cohort of older adults who had been exposed to, but avoided, a potentially exploitative situation (n = 13, 7 female) were evaluated. Using magnetic resonance imaging, we examined cortical thickness and resting state functional connectivity. Behavioral data were collected using standardized cognitive assessments, self-report measures of mood and social functioning. RESULTS: The exploited group showed cortical thinning in anterior insula and posterior superior temporal cortices, regions associated with processing affective and social information, respectively. Functional connectivity encompassing these regions, within default and salience networks, was reduced, while between network connectivity was increased. Self-reported anger and hostility was higher for the exploited group. CONCLUSIONS: We observed financial exploitation associated with brain differences in regions involved in socioemotional functioning. These exploratory and preliminary findings suggest that alterations in brain regions implicated in socioemotional functioning may be a marker of financial exploitation risk. Large-scale, prospective studies are necessary to validate this neural mechanism, and develop predictive markers for use in clinical practice.

Synthesis and Characterization of a Two Stage, Nonlinear Photobase Generator.

Amine photobase generators (PBGs) are uncommon yet useful compounds. Rarer still are examples of PBGs that are active at visible wavelengths. We report the synthesis and characterization of new photolabile amine protecting groups that are active under visible light. The new chromophore, benzothiophene imino-phenylacetonitrile (BTIPA), was synthesized in four steps without use of chromatography and found to release any one of several amines upon exposure to 405 nm light. The chromophore was also demonstrated to be useful as a Merrifield synthesis protecting group. Experimental evidence suggests a sequential, two stage photolysis mechanism which leads to a nonlinear response to dose.

Patterns of preserved and impaired spatial memory in a case of developmental amnesia.

The hippocampus is believed to have evolved to support allocentric spatial representations of environments as well as the details of personal episodes that occur within them, whereas other brain structures are believed to support complementary egocentric spatial representations. Studies of patients with adult-onset lesions lend support to these distinctions for newly encountered places but suggest that with time and/or experience, schematic aspects of environments can exist independent of the hippocampus. Less clear is the quality of spatial memories acquired in individuals with impaired episodic memory in the context of a hippocampal system that did not develop normally. Here we describe a detailed investigation of the integrity of spatial representations of environments navigated repeatedly over many years in the rare case of H.C., a person with congenital absence of the mammillary bodies and abnormal hippocampal and fornix development. H.C. and controls who had extensive experience navigating the residential and downtown areas known to H.C. were tested on mental navigation tasks that assess the identity, location, and spatial relations among landmarks, and the ability to represent routes. H.C. was able to represent distances and directions between familiar landmarks and provide accurate, though inefficient, route descriptions. However, difficulties producing detailed spatial features on maps and accurately ordering more than two landmarks that are in close proximity to one another along a route suggest a spatial representation that includes only coarse, schematic information that lacks coherence and that cannot be used flexibly. This pattern of performance is considered in the context of other areas of preservation and impairment exhibited by H.C. and suggests that the allocentric-egocentric dichotomy with respect to hippocampal and extended hippocampal system function may need to be reconsidered.