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Study Design: Literature Review., Objective: The goal of this study was to provide a comprehensive outline of spinal injuries that may transpire over the course of military service from traumatic to repetitive stress injuries and chronic sequalae. We considered studies that assessed spinal injuries in the combat and non-combat settings as reported in the literature over the last 15-20 years., Summary of Background Data: Military service places servicemembers under substantial physical demands, while also exposing them to dangerous, unpredictable environments. As a result, servicemembers are at an increased risk of spinal injuries from combat-related trauma and other causes. They may have different care needs and recovery profiles when compared to civilians with spinal disorders., Methods: We performed a review of the available literature on spinal injuries and spinal care in the Military Health System from 2001-present., Results: The studies discussed in this review were primarily focused on the conflicts in both Iraq and Afghanistan from over ten years ago and do not fully capture the present-day advancements in military technology that may have an impact on the potential for spinal injuries. The long-term effects of sustained military service and the relative influence of high demand versus sedentary military occupations on the development of spinal disorders remains poorly understood. Given the changing nature of military service, both with respect to the demographic in uniform and the ever-evolving nature of modern combat, we believe that only a long-term prospective observational study dedicated to the surveillance of spinal problems could effectively answer these questions., Conclusion: Further research into the present-day characterization of spinal injuries is warranted given the advancements in both military technology and spine care that have occurred over the last ten years., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background Context: Expandable transforaminal lumbar interbody fusion (TLIF) cages have become popular in recent years due to anticipated advantages of increased disc height, improved segmental lordosis, and ease of implantation. Such benefits have not been conclusively demonstrated in the literature., Purpose: To determine whether expandable cages increase disc height and segmental lordosis in a durable way following surgery and compare complication profiles between cage types., Study Design/setting: Retrospective cohort study conducted within a large academic health system involving 31 different spine surgeons., Patient Sample: Adults undergoing single-level TLIF for an indication other than infection, tumor, trauma, or revision instrumentation from 2021 to 2023., Outcome Measures: Our primary outcomes were changes in segmental disc height, segmental lordosis, and L4-S1 lordosis at 2 weeks, 6 months, and 1 year following surgery relative to baseline. Our secondary outcomes were frequencies of incidental durotomies, surgical site infections, readmissions, death, subsidence, and unplanned return to the operating room., Methods: Radiographic variables were collected from our institutional imaging registry. Demographics and surgical characteristics were abstracted from chart review. Generalized linear modeling was used for each primary outcome, with cage type (expandable vs. static) as our primary predictor and age, biologic sex, race, CCI, year of surgery, duration of surgery, invasiveness of surgery, surgeon specialty (Orthopedics vs. Neurosurgery), and level of surgery as covariates., Results: Our cohort consisted of 417 patients with a mean age of 62. Static cages were used in 306 patients and expandable cages in 111. Expandable cages were associated with increased changes in disc height relative to static cages at 2 weeks (1.1 mm [0.2-1.9]; p=.01) and 6 months (1.2 mm [0.2-2.3]; p=.02) following surgery, but differences were no longer significant at 1 year (0.4 mm [-0.9-1.8]; p=.4). Expandable cages were found to subside more commonly than static cages (14.1% vs. 6.6%; p=.04). No significant differences between cage types were identified in lordotic parameters at any timepoint (p=0.25 to p=0.97)., Conclusions: Expandable cages were associated with an initial increase in disc height relative to static cages, but this difference diminished with the first year of surgery, likely due to a higher rate of subsidence within the expandable cohort., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Importance: The incidence of chronic pain has been increasing over the last decades and may be associated with the stress of deployment in active-duty servicewomen (ADSW) as well as women civilian dependents whose spouse or partner served on active duty., Objective: To assess incidence of chronic pain among active-duty servicewomen and women civilian dependents with service during 2006 to 2013 compared with incidence among like individuals at a time of reduced combat exposure and deployment intensity (2014-2020)., Design, Setting, and Participants: This cohort study used claims data from the Military Health System data repository to identify ADSW and dependents who were diagnosed with chronic pain. The incidence of chronic pain among individuals associated with service during 2006 to 2013 was compared with 2014 to 2020 incidence. Data were analyzed from September 2023 to April 2024., Main Outcomes and Measures: The primary outcome was the diagnosis of chronic pain. Multivariable logistic regression analyses were used to adjust for confounding, and secondary analyses were performed to account for interactions between time period and proxies for socioeconomic status and combat exposure., Results: A total of 3 473 401 individuals (median [IQR] age, 29.0 [22.0-46.0] years) were included, with 644 478 ADSW (18.6%). Compared with ADSW in 2014 to 2020, ADSW in 2006 to 2013 had significantly increased odds of chronic pain (odds ratio [OR], 1.53; 95% CI, 1.48-1.58). The odds of chronic pain among dependents in 2006 to 2013 was also significantly higher compared with dependents from 2014 to 2020 (OR, 1.96; 95% CI, 1.93-1.99). The proxy for socioeconomic status was significantly associated with an increased odds of chronic pain (2006-2013 junior enlisted ADSWs: OR, 1.95; 95% CI, 1.83-2.09; 2006-2013 junior enlisted dependents: OR, 3.05; 95% CI, 2.87-3.25)., Conclusions and Relevance: This cohort study found significant increases in the diagnosis of chronic pain among ADSW and civilian dependents affiliated with the military during a period of heightened deployment intensity (2006-2013). The effects of disparate support structures, coping strategies, stress regulation, and exposure to military sexual trauma may apply to both women veterans and civilian dependents.

Photonic technologies promise to deliver quantitative, multiplex, and inexpensive medical diagnostic platforms by leveraging the highly scalable processes developed for the fabrication of semiconductor microchips. However, in practice, the affordability of these platforms is limited by complex and expensive sample handling and optical alignment. We previously reported the development of a disposable photonic assay that incorporates inexpensive plastic micropillar microfluidic cards for sample delivery. That system as developed was limited to singleplex assays due to its optical configuration. To enable multiplexing, we report a new approach addressing multiplex light I/O, in which the outputs of individual grating couplers on a photonic chip are mapped to fibers in a fiber bundle. As demonstrated in the context of detecting antibody responses to influenza and SARS-CoV-2 antigens in human serum and saliva, this enables multiplexing in an inexpensive, disposable, and compact format.

Surgical intervention is often recommended for refractory pathology affecting the biceps-labrum complex. Tenodesis of the long head of the biceps tendon (LHBT) is a widely accepted treatment modality; however, the optimal technique remains elusive. Arthroscopic subdeltoid transfer of the LHBT to the conjoint tendon, as described in this technical note, continues to demonstrate excellent clinical results. Its advantages include soft tissue-to-soft tissue healing, an advantageous biomechanical construct, and comprehensive evaluation and decompression of the LHBT including the extra-articular bicipital tunnel. The primary limitation of this procedure is the perceived learning curve for safe navigation within the subdeltoid space., (© 2023 The Authors.)

Tau-mediated toxicity is associated with cognitive decline and Alzheimer's disease (AD) progression. In particular, tau post-translational modifications (PTMs) are thought to generate aberrant tau species resulting in neuronal dysfunction. Despite being well characterized in postmortem AD brain, it is unclear how caspase-mediated C-terminal tau cleavage promotes neurodegeneration, as few studies have developed the models to dissect this pathogenic mechanism. Here, we show that proteasome impairment results in cleaved tau accumulation at the post-synaptic density (PSD), a process that is modulated by neuronal activity. Cleaved tau (at residue D421) impairs neuronal firing and causes inefficient initiation of network bursts, consistent with reduced excitatory drive. We propose that reduced neuronal activity, or silencing, is coupled to proteasome dysfunction, which drives cleaved tau accumulation at the PSD and subsequent synaptotoxicity. Our study connects three common themes in the progression of AD: impaired proteostasis, caspase-mediated tau cleavage, and synapse degeneration., Competing Interests: The authors declare no competing interest with the contents of this article., (© 2023 The Author(s).)

Wearable, mobile, and point-of-care (POC) sensors comprise a rapidly expanding field of devices aimed at improving human health by relaying real-time biometric data such as heart rate and glucose levels. The current scope of what these devices can offer healthcare is limited by their inability to measure biomarkers associated with inflammation, well-being, and disease. Photonic biosensors that integrate sensing elements directly with spectrometers, lasers, and detectors are an attractive approach to enabling POC sensors, with distinct advantages in terms of size, weight, power consumption, and cost. Here, we have demonstrated for the first time the integration of photonic microring resonator biosensors with an on-chip microring filter bank spectrometer for the controlled detection of inflammatory biomarker C-reactive protein (CRP) in serum. We demonstrate that sensor and spectrometer performance is tolerant of temperature variation, as temperature dependence moves in parallel. Finally, we assess the impact of manufacturing variability on the 300 mm wafer scale on the performance of the spectrometer. Taken together, these results suggest that integration of on-chip ring filter bank spectrometers with ring resonator-based biosensors constitutes an attractive approach toward cost-effective integrated sensor development.

Tissue chip (TC) devices, also known as microphysiological systems (MPS) or organ chips (OCs or OoCs), seek to mimic human physiology on a small scale. They are intended to improve upon animal models in terms of reproducibility and human relevance, at a lower monetary and ethical cost. Virtually all TC systems are analyzed at an endpoint, leading to widespread recognition that new methods are needed to enable sensing of specific biomolecules in real time, as they are being produced by the cells. To address this need, we incorporated photonic biosensors for inflammatory cytokines into a model TC. Human bronchial epithelial cells seeded in a microfluidic device were stimulated with lipopolysaccharide, and the cytokines secreted in response sensed in real time. Sensing analyte transport through the TC in response to disruption of tissue barrier was also demonstrated. This work demonstrates the first application of photonic sensors to a human TC device, and will enable new applications in drug development and disease modeling.

Decades of research have shown that biosensors using photonic circuits fabricated using CMOS processes can be highly sensitive, selective, and quantitative. Unfortunately, the cost of these sensors combined with the complexity of sample handling systems has limited the use of such sensors in clinical diagnostics. We present a new "disposable photonics" sensor platform in which rice-sized (1 × 4 mm) silicon nitride ring resonator sensor chips are paired with plastic micropillar fluidic cards for sample handling and optical detection. We demonstrate the utility of the platform in the context of detecting human antibodies to SARS-CoV-2, both in convalescent COVID-19 patients and for subjects undergoing vaccination. Given its ability to provide quantitative data on human samples in a simple, low-cost single-use format, we anticipate that this platform will find broad utility in clinical diagnostics for a broad range of assays.

Detection of antibodies to upper respiratory pathogens is critical to surveillance, assessment of the immune status of individuals, vaccine development, and basic biology. The urgent need for antibody detection tools has proven particularly acute in the COVID-19 era. We report a multiplex label-free antigen microarray on the Arrayed Imaging Reflectometry (AIR) platform for detection of antibodies to SARS-CoV-2, SARS-CoV-1, MERS, three circulating coronavirus strains (HKU1, 229E, OC43) and three strains of influenza. We find that the array is readily able to distinguish uninfected from convalescent COVID-19 subjects, and provides quantitative information about total Ig, as well as IgG- and IgM-specific responses., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Manganese (Mn) is an essential metal, but excessive exposures have been well-documented to culminate in neurotoxicity. Curiously, the precise mechanisms of Mn neurotoxicity are still unknown. One hypothesis suggests that Mn exerts its toxicity by inhibiting mitochondrial function, which then (if exposure levels are high and long enough) leads to cell death. Here, we used a Huntington's disease cell model with known differential sensitivities to manganese-STHdhQ7/Q7 and STHdhQ111/Q111 cells-to examine the effects of acute Mn exposure on mitochondrial function. We determined toxicity thresholds for each cell line using both changes in cell number and caspase-3/7 activation. We used a range of acute Mn exposures (0-300 µM), both above and below the cytotoxic threshold, to evaluate mitochondria-associated metabolic balance, mitochondrial respiration, and substrate dependence. In both cell lines, we observed no effect on markers of mitochondrial function at subtoxic Mn exposures (below detectable levels of cell death), yet at supratoxic exposures (above detectable levels of cell death) mitochondrial function significantly declined. We validated these findings in primary striatal neurons. In cell lines, we further observed that subtoxic Mn concentrations do not affect glycolytic function or major intracellular metabolite quantities. These data suggest that in this system, Mn exposure impairs mitochondrial function only at concentrations coincident with or above the initiation of cell death and is not consistent with the hypothesis that mitochondrial dysfunction precedes or induces Mn cytotoxicity., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Epidemiological and clinical studies have long shown that exposure to high levels of heavy metals are associated with increased risks of neurodegenerative diseases. It is widely accepted that autophagic dysfunction is involved in pathogenesis of various neurodegenerative disorders; however, the role of heavy metals in regulation of macroautophagy/autophagy is unclear. Here, we show that manganese (Mn) induces a decline in nuclear localization of TFEB (transcription factor EB), a master regulator of the autophagy-lysosome pathway, leading to autophagic dysfunction in astrocytes of mouse striatum. We further show that Mn exposure suppresses autophagic-lysosomal degradation of mitochondria and induces accumulation of unhealthy mitochondria. Activation of autophagy by rapamycin or TFEB overexpression ameliorates Mn-induced mitochondrial respiratory dysfunction and reactive oxygen species (ROS) generation in astrocytes, suggesting a causal relation between autophagic failure and mitochondrial dysfunction in Mn toxicity. Taken together, our data demonstrate that Mn inhibits TFEB activity, leading to impaired autophagy that is causally related to mitochondrial dysfunction in astrocytes. These findings reveal a previously unappreciated role for Mn in dysregulation of autophagy and identify TFEB as a potential therapeutic target to mitigate Mn toxicity., Abbreviations: BECN1: beclin 1; CTSD: cathepsin D; DMEM: Dulbecco's Modified Eagle Medium; GFAP: glial fibrillary acid protein; GFP: green fluorescent protein; HBSS: hanks balanced salt solution; LAMP: lysosomal-associated membrane protein; LDH: lactate dehydrogenase; Lys Inh: lysosomal inhibitors; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; Mn: manganese; MTOR: mechanistic target of rapamycin kinase; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; PFA: paraformaldehyde; PI: propidium iodide; ROS: reactive oxygen species; s.c.: subcutaneous; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TFEB: transcription factor EB.

Perturbations in insulin/IGF signaling and manganese (Mn 2+ ) uptake and signaling have been separately reported in Huntington's disease (HD) models. Insulin/IGF supplementation ameliorates HD phenotypes via upregulation of AKT, a known Mn 2+ -responsive kinase. Limited evidence both in vivo and in purified biochemical systems suggest Mn 2+ enhances insulin/IGF receptor (IR/IGFR), an upstream tyrosine kinase of AKT. Conversely, Mn 2+ deficiency impairs insulin release and associated glucose tolerance in vivo. Here, we test the hypothesis that Mn 2+ -dependent AKT signaling is predominantly mediated by direct Mn 2+ activation of the insulin/IGF receptors, and HD-related impairments in insulin/IGF signaling are due to HD genotype-associated deficits in Mn 2+ bioavailability. We examined the combined effects of IGF-1 and/or Mn 2+ treatments on AKT signaling in multiple HD cellular models. Mn 2+ treatment potentiates p-IGFR/IR-dependent AKT phosphorylation under physiological (1 nM) or saturating (10 nM) concentrations of IGF-1 directly at the level of intracellular activation of IGFR/IR. Using a multi-pharmacological approach, we find that > 70-80% of Mn 2+ -associated AKT signaling across rodent and human neuronal cell models is specifically dependent on IR/IGFR, versus other signaling pathways upstream of AKT activation. Mn 2+ -induced p-IGFR and p-AKT were diminished in HD cell models, and, consistent with our hypothesis, were rescued by co-treatment of Mn 2+ and IGF-1. Lastly, Mn 2+ -induced IGF signaling can modulate HD-relevant biological processes, as the reduced glucose uptake in HD STHdh cells was partially reversed by Mn 2+ supplementation. Our data demonstrate that Mn 2+ supplementation increases peak IGFR/IR-induced p-AKT likely via direct effects on IGFR/IR, consistent with its role as a cofactor, and suggests reduced Mn 2+ bioavailability contributes to impaired IGF signaling and glucose uptake in HD models.

The molecular etiology linking the pathogenic mutations in the Huntingtin (Htt) gene with Huntington's disease (HD) is unknown. Prior work suggests a role for Htt in neuronal autophagic function and mutant HTT protein disrupts autophagic cargo loading. Reductions in the bioavailability of the essential metal manganese (Mn) are seen in models of HD. Excess cellular Mn impacts autophagic function, but the target and molecular basis of these changes are unknown. Thus, we sought to determine if changes in cellular Mn status impact autophagic processes in a wild-type or mutant Htt-dependent manner. We report that the HD genotype is associated with reduced Mn-induced autophagy and that acute Mn exposure increases autophagosome induction/formation. To determine if a deficit in bioavailable Mn is mechanistically linked to the autophagy-related HD cellular phenotypes, we examined autophagosomes by electron microscopy. We observed that a 24 h 100 uM Mn restoration treatment protocol attenuated an established HD 'cargo-recognition failure' in the STHdh HD model cells by increasing the percentage of filled autophagosomes. Mn restoration had no effect on HTT aggregate number, but a 72 h co-treatment with chloroquine (CQ) in GFP-72Q-expressing HEK293 cells increased the number of visible aggregates in a dose-dependent manner. As CQ prevents autophagic degradation this indicates that Mn restoration in HD cell models facilitates incorporation of aggregates into autophagosomes. Together, these findings suggest that defective Mn homeostasis in HD models is upstream of the impaired autophagic flux and provide proof-of-principle support for increasing bioavailable Mn in HD to restore autophagic function and promote aggregate clearance., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

In a recent study, we found that blocking the protein kinase ataxia telangiectasia mutated (ATM) with the small molecule inhibitor (SMI) KU-55933 can completely abrogate Mn-induced phosphorylation of p53 at serine 15 (p-p53) in human induced pluripotent stem cell (hiPSC)-differentiated striatal neuroprogenitors. However, in the immortalized mouse striatal progenitor cell line STHdh Q7/Q7 , a concentration of KU55933 far exceeding its IC 50 for ATM was required to inhibit Mn-induced p-p53. This suggested an alternative signaling system redundant with ATM kinase for activating p53 in this cell line- one that was altered by KU55933 at these higher concentrations (i.e. mTORC1, DNApk, PI3K). To test the hypothesis that one or more of these signaling pathways contributed to Mn-induced p-p53, we utilized a set of SMIs (e.g. NU7441 and LY294002) known to block DNApk, PI3K, and mTORC1 at distinct concentrations. We found that the SMIs inhibit Mn-induced p-p53 expression near the expected IC 50s for PI3K, versus other known targets. We hypothesized that inhibiting PI3K reduces intracellular Mn and thereby decreases activation of p53 by Mn. Using the cellular fura-2 manganese extraction assay (CFMEA), we determined that KU55933/60019, NU7441, and LY294002 (at concentrations near their IC 50s for PI3K) all decrease intracellular Mn (∼50%) after a dual, 24-h Mn and SMI exposure. Many pathways are activated by Mn aside from p-p53, including AKT and mTOR pathways. Thus, we explored the activation of these pathways by Mn in STHdh cells as well as the effects of other pathway inhibitors. p-AKT and p-S6 activation by Mn is almost completely blocked upon addition of NU7441(5μM) or LY294002(7μM), supporting PI3K's upstream role in the AKT/mTOR pathway. We also investigated whether PI3K inhibition blocks Mn uptake in other cell lines. LY294002 exposure did not reduce Mn uptake in ST14A, Neuro2A, HEK293, MEF, or hiPSC-derived neuroprogenitors. Next, we sought to determine whether inhibition of PI3K blocked p53 phosphorylation by directly blocking an unknown PI3K/p53 interaction or indirectly reducing intracellular Mn, decreasing p-p53 expression. In-Cell Western and CFMEA experiments using multiple concentrations of Mn exposures demonstrated that intracellular Mn levels directly correlated with p-p53 expression with or without addition of LY294002. Finally, we examined whether PI3K inhibition was able to block Mn-induced p-p53 activity in hiPSC-derived striatal neuroprogenitors. As expected, LY294002 does not block Mn-induced p-p53 as PI3K inhibition is unable to reduce Mn net uptake in this cell line, suggesting the effect of LY294002 on Mn uptake is relatively specific to the STHdh mouse striatal cell line., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease resulting in motor impairment and death in patients. Recently, several studies have demonstrated insulin or insulin-like growth factor (IGF) treatment in models of HD, resulting in potent amelioration of HD phenotypes via modulation of the PI3K/AKT/mTOR pathways. Administration of IGF and insulin can rescue microtubule transport, metabolic function, and autophagy defects, resulting in clearance of Huntingtin (HTT) aggregates, restoration of mitochondrial function, amelioration of motor abnormalities, and enhanced survival. Manganese (Mn) is an essential metal to all biological systems but, in excess, can be toxic. Interestingly, several studies have revealed the insulin-mimetic effects of Mn-demonstrating Mn can activate several of the same metabolic kinases and increase peripheral and neuronal insulin and IGF-1 levels in rodent models. Separate studies have shown mouse and human striatal neuroprogenitor cell (NPC) models exhibit a deficit in cellular Mn uptake, indicative of a Mn deficiency. Furthermore, evidence from the literature reveals a striking overlap between cellular consequences of Mn deficiency (i.e., impaired function of Mn-dependent enzymes) and known HD endophenotypes including excitotoxicity, increased reactive oxygen species (ROS) accumulation, and decreased mitochondrial function. Here we review published evidence supporting a hypothesis that (1) the potent effect of IGF or insulin treatment on HD models, (2) the insulin-mimetic effects of Mn, and (3) the newly discovered Mn-dependent perturbations in HD may all be functionally related. Together, this review will present the intriguing possibility that intricate regulatory cross-talk exists between Mn biology and/or toxicology and the insulin/IGF signaling pathways which may be deeply connected to HD pathology and, perhaps, other neurodegenerative diseases (NDDs) and other neuropathological conditions.

Alterations in DNA damage response and repair have been observed in Huntington's disease (HD). We generated induced pluripotent stem cells (iPSC) from primary dermal fibroblasts of 5 patients with HD and 5 control subjects. A significant fraction of the HD iPSC lines had genomic abnormalities as assessed by karyotype analysis, while none of our control lines had detectable genomic abnormalities. We demonstrate a statistically significant increase in genomic instability in HD cells during reprogramming. We also report a significant association with repeat length and severity of this instability. Our karyotypically normal HD iPSCs also have elevated ATM-p53 signaling as shown by elevated levels of phosphorylated p53 and H2AX, indicating either elevated DNA damage or hypersensitive DNA damage signaling in HD iPSCs. Thus, increased DNA damage responses in the HD genotype is coincidental with the observed chromosomal aberrations. We conclude that the disease causing mutation in HD increases the propensity of chromosomal instability relative to control fibroblasts specifically during reprogramming to a pluripotent state by a commonly used episomal-based method that includes p53 knockdown.

The essential micronutrient manganese is enriched in brain, especially in the basal ganglia. We sought to identify neuronal signaling pathways responsive to neurologically relevant manganese levels, as previous data suggested that alterations in striatal manganese handling occur in Huntington's disease (HD) models. We found that p53 phosphorylation at serine 15 is the most responsive cell signaling event to manganese exposure (of 18 tested) in human neuroprogenitors and a mouse striatal cell line. Manganese-dependent activation of p53 was severely diminished in HD cells. Inhibitors of ataxia telangiectasia mutated (ATM) kinase decreased manganese-dependent phosphorylation of p53. Likewise, analysis of ATM autophosphorylation and additional ATM kinase targets, H2AX and CHK2, support a role for ATM in the activation of p53 by manganese and that a defect in this process occurs in HD. Furthermore, the deficit in Mn-dependent activation of ATM kinase in HD neuroprogenitors was highly selective, as DNA damage and oxidative injury, canonical activators of ATM, did not show similar deficits. We assessed cellular manganese handling to test for correlations with the ATM-p53 pathway, and we observed reduced Mn accumulation in HD human neuroprogenitors and HD mouse striatal cells at manganese exposures associated with altered p53 activation. To determine if this phenotype contributes to the deficit in manganese-dependent ATM activation, we used pharmacological manipulation to equalize manganese levels between HD and control mouse striatal cells and rescued the ATM-p53 signaling deficit. Collectively, our data demonstrate selective alterations in manganese biology in cellular models of HD manifest in ATM-p53 signaling., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Introduction: Acute kidney injury (AKI) is common after cardiac operations. There are different risk factors or determinants of AKI, and some are related to cardiopulmonary bypass (CPB). In this study, we explored the association between metabolic parameters (oxygen delivery (DO2) and carbon dioxide production (VCO2)) during CPB with postoperative AKI., Methods: We conducted a retrospective analysis of prospectively collected data at two different institutions. The study population included 359 adult patients. The DO2 and VCO2 levels of each patient were monitored during CPB. Outcome variables were related to kidney function (peak postoperative serum creatinine increase and AKI stage 1 or 2). The experimental hypothesis was that nadir DO2 values and nadir DO2/VCO2 ratios during CPB would be independent predictors of AKI. Multivariable logistic regression models were built to detect the independent predictors of AKI and any kind of kidney function damage., Results: A nadir DO2 level < 262 mL/minute/m2 and a nadir DO2/VCO2 ratio < 5.3 were independently associated with AKI within a model including EuroSCORE and CPB duration. Patients with nadir DO2 levels and nadir DO2/VCO2 ratios below the identified cutoff values during CPB had a significantly higher rate of AKI stage 2 (odds ratios 3.1 and 2.9, respectively). The negative predictive power of both variables exceeded 90%. The most accurate predictor of AKI stage 2 postoperative status was the nadir DO2 level., Conclusions: The nadir DO2 level during CPB is independently associated with postoperative AKI. The measurement of VCO2-related variables does not add accuracy to the AKI prediction. Since DO2 during CPB is a modifiable factor (through pump flow adjustments), this study generates the hypothesis that goal-directed perfusion management aimed at maintaining the DO2 level above the identified critical value might limit the incidence of postoperative AKI.

The incidence of acquired brain injury in infants and pre-school children is increasing, creating new challenges for assessment and intervention. This paper presents a context for assessment and interventions by describing the developmental effects of traumatic brain injury in young children, from birth to the age of 5 years. A review of the literature on the developmental and learning issues of the infants, toddlers and young children who sustain traumatic brain injury is presented. Information on resources including the federally-funded, state-administered Infant and Toddler and Pre-school Programs is included, along with suggestions for interventions.