Potential neural substrates underlying circadian and olfactory disruptions in preclinical Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of dementia, with over 45 million patients worldwide, and poses significant economic and emotional burdens to both patients and caregivers, significantly raising the number of those affected. Unfortunately, much of the existing research on the disease only addresses a small subset of associated symptomologies and pathologies. In this review, we propose to target the earliest stages of the disease, when symptomology first arises. In these stages, before the onset of hallmark symptoms of AD such as cognitive impairments and memory loss, circadian and olfactory disruptions arise and are detectable. Functional similarities between circadian and olfactory systems provide a basis upon which to seek out common mechanisms in AD which may target them early on in the disease. Existing studies of interactions between these systems, while intriguing, leave open the question of the neural substrates underlying them. Potential substrates for such interactions are proposed in this review, such as indirect projections that may functionally connect the two systems and dopaminergic signaling. These substrates may have significant implications for mechanisms underlying disruptions to circadian and olfactory function in early stages of AD. In this review, we propose early detection of AD using a combination of circadian and olfactory deficits and subsequent early treatment of these deficits may provide profound benefits to both patients and caregivers. Additionally, we suggest that targeting research toward the intersection of these two systems in AD could uncover mechanisms underlying the broader set of symptoms and pathologies that currently elude researchers.

A brainstem to circadian system circuit links Tau pathology to sundowning-related disturbances in an Alzheimer's disease mouse model.

Alzheimer's disease (AD) patients exhibit progressive disruption of entrained circadian rhythms and an aberrant circadian input pathway may underlie such dysfunction. Here we examine AD-related pathology and circadian dysfunction in the APPSwe-Tau (TAPP) model of AD. We show these mice exhibit phase delayed body temperature and locomotor activity with increases around the active-to-rest phase transition. Similar AD-related disruptions are associated with sundowning, characterized by late afternoon and early evening agitation and aggression, and we show TAPP mice exhibit increased aggression around this transition. We show such circadian dysfunction and aggression coincide with hyperphosphorylated Tau (pTau) development in lateral parabrachial (LPB) neurons, with these disturbances appearing earlier in females. Finally, we show LPB neurons, including those expressing dynorphin (LPBdyn), project to circadian structures and are affected by pTau, and LPBdyn ablations partially recapitulate the hyperthermia of TAPP mice. Altogether we link pTau in a brainstem circadian input pathway to AD-related disturbances relevant to sundowning.

Voluntary Wheel Running Exercise Does Not Attenuate Circadian and Cardiac Dysfunction Caused by Conditional Deletion of Bmal1.

Circadian misalignment occurs with age, jet lag, and shift work, leading to maladaptive health outcomes including cardiovascular diseases. Despite the strong link between circadian disruption and heart disease, the cardiac circadian clock is poorly understood, prohibiting identification of therapies to restore the broken clock. Exercise is the most cardioprotective intervention identified to date and has been suggested to reset the circadian clock in other peripheral tissues. Here, we tested the hypothesis that conditional deletion of core circadian gene Bmal1 would disrupt cardiac circadian rhythm and function and that this disruption would be ameliorated by exercise. To test this hypothesis, we generated a transgenic mouse with spatial and temporal deletion of Bmal1 only in adult cardiac myocytes (Bmal1 cardiac knockout [cKO]). Bmal1 cKO mice demonstrated cardiac hypertrophy and fibrosis concomitant with impaired systolic function. This pathological cardiac remodeling was not rescued by wheel running. While the molecular mechanisms responsible for the profound cardiac remodeling are unclear, it does not appear to involve activation of the mammalian target of rapamycin (mTOR) signaling or changes in metabolic gene expression. Interestingly, cardiac deletion of Bmal1 disrupted systemic rhythms as evidenced by changes in the onset and phasing of activity in relationship to the light/dark cycle and by decreased periodogram power as measured by core temperature, suggesting cardiac clocks can regulate systemic circadian output. Together, we suggest a critical role for cardiac Bmal1 in regulating both cardiac and systemic circadian rhythm and function. Ongoing experiments will determine how disruption of the circadian clock causes cardiac remodeling in an effort to identify therapeutics to attenuate the maladaptive outcomes of a broken cardiac circadian clock.

Median preoptic GABA and glutamate neurons exert differential control over sleep behavior.

Previous studies suggest that the median preoptic nucleus (MnPO) of the hypothalamus plays an important role in regulating the wake-sleep cycle and, in particular, homeostatic sleep drive. However, the precise cellular phenotypes, targets, and central mechanisms by which the MnPO neurons regulate the wake-sleep cycle remain unknown. Both excitatory and inhibitory MnPO neurons innervate brain regions implicated in sleep promotion and maintenance, suggesting that both cell types may participate in sleep control. Using genetically targeted approaches, we investigated the role of the MnPO GABAergic (MnPOVgat) and glutamatergic (MnPOVglut2) neurons in modulating wake-sleep behavior of mice. We found that both neuron populations differentially participate in wake-sleep control, with MnPOVgat neurons being involved in sleep homeostasis and MnPOVglut2 neurons facilitating sleep during allostatic (stressful) challenges.

Case report: Hyperosmolar hyperglycemic syndrome secondary to PEG-asparaginase-induced hypertriglyceridemia and pancreatitis.

Pegylated (PEG)-asparaginase is an established treatment for acute lymphoblastic leukemias that exhibits an antitumor effect by depleting asparagine, an amino acid essential for leukemia cell protein synthesis. Pancreatitis with hypertriglyceridemia is a well-established toxidrome associated with PEG-asparaginase. However, impaired pancreatic synthetic function and hormone release have rarely been reported as a result of PEG-asparaginase pancreatitis. In this report, we present a 22-year-old woman recently diagnosed with T-acute lymphoblastic leukemia (T-ALL), who presented to the hospital with progressive weakness, confusion, blurry vision, hallucinations, and abdominal pain after induction treatment with daunorubicin, vincristine, PEG-asparaginase, and dexamethasone following the AYA protocol. She was found to have hypertriglyceridemia, acute pancreatitis, and hyperosmolar hyperglycemic syndrome. While pancreatitis and hypertriglyceridemia are commonly reported side effects of PEG-asparaginase, HHS related to these conditions has been sparsely reported. Providers should maintain awareness of this association and consider routine serial glucose monitoring of patients receiving PEG-asparaginase.

Management of hepatotoxicity of chemotherapy and targeted agents.

Hepatotoxicity of chemotherapeutic agents such as methotrexate, oxaliplatin, and irinotecan have been well documented and characterized allowing for careful management by oncologists during administration. However, the rapid advance of the field of oncology and introduction of new classes of therapies such as small molecule inhibitors and immunotherapies have introduced new hepatotoxicity challenges and management strategies. This work is a compilation of the hepatotoxicity and recommended management of various chemotherapies and targeted agents, with a focus on the newer classes of targeted anticancer agents.

Systems and Circuits Linking Chronic Pain and Circadian Rhythms.

Research over the last 20 years regarding the link between circadian rhythms and chronic pain pathology has suggested interconnected mechanisms that are not fully understood. Strong evidence for a bidirectional relationship between circadian function and pain has been revealed through inflammatory and immune studies as well as neuropathic ones. However, one limitation of many of these studies is a focus on only a few molecules or cell types, often within only one region of the brain or spinal cord, rather than systems-level interactions. To address this, our review will examine the circadian system as a whole, from the intracellular genetic machinery that controls its timing mechanism to its input and output circuits, and how chronic pain, whether inflammatory or neuropathic, may mediate or be driven by changes in these processes. We will investigate how rhythms of circadian clock gene expression and behavior, immune cells, cytokines, chemokines, intracellular signaling, and glial cells affect and are affected by chronic pain in animal models and human pathologies. We will also discuss key areas in both circadian rhythms and chronic pain that are sexually dimorphic. Understanding the overlapping mechanisms and complex interplay between pain and circadian mediators, the various nuclei they affect, and how they differ between sexes, will be crucial to move forward in developing treatments for chronic pain and for determining how and when they will achieve their maximum efficacy.

Cardiotoxicity of chemotherapy and targeted agents.

The evolution of cancer treatment and development of new classes of anticancer therapies have continued to revolutionize the field of oncology. New therapies including targeted agents, immunotherapies, and adoptive cell transfer have allowed for exciting survival benefit progress for patients. However, the novel nature of these therapies as well as the longer survival periods of patients receiving them has highlighted the various side effects of anticancer therapies. Cardiotoxicity has emerged as a major side effect of anticancer treatment and can present both acutely during treatment and chronically even years after treatment has been completed. This work compiles the cardiotoxic side effects of various chemotherapeutic and targeted anticancer therapies and their management.

Potential Pathways for Circadian Dysfunction and Sundowning-Related Behavioral Aggression in Alzheimer's Disease and Related Dementias.

Patients with Alzheimer's disease (AD) and related dementias are commonly reported to exhibit aggressive behavior and other emotional behavioral disturbances, which create a tremendous caretaker burden. There has been an abundance of work highlighting the importance of circadian function on mood and emotional behavioral regulation, and recent evidence demonstrates that a specific hypothalamic pathway links the circadian system to neurons that modulate aggressive behavior, regulating the propensity for aggression across the day. Such shared circuitry may have important ramifications for clarifying the complex interactions underlying "sundowning syndrome," a poorly understood (and even controversial) clinical phenomenon in AD and dementia patients that is characterized by agitation, aggression, and delirium during the late afternoon and early evening hours. The goal of this review is to highlight the potential output and input pathways of the circadian system that may underlie circadian dysfunction and behavioral aggression associated with sundowning syndrome, and to discuss possible ways these pathways might inform specific interventions for treatment. Moreover, the apparent bidirectional relationship between chronic disruptions of circadian and sleep-wake regulation and the pathology and symptoms of AD suggest that understanding the role of these circuits in such neurobehavioral pathologies could lead to better diagnostic or even preventive measures.

Suprachiasmatic VIP neurons are required for normal circadian rhythmicity and comprised of molecularly distinct subpopulations.

The hypothalamic suprachiasmatic (SCN) clock contains several neurochemically defined cell groups that contribute to the genesis of circadian rhythms. Using cell-specific and genetically targeted approaches we have confirmed an indispensable role for vasoactive intestinal polypeptide-expressing SCN (SCNVIP) neurons, including their molecular clock, in generating the mammalian locomotor activity (LMA) circadian rhythm. Optogenetic-assisted circuit mapping revealed functional, di-synaptic connectivity between SCNVIP neurons and dorsomedial hypothalamic neurons, providing a circuit substrate by which SCNVIP neurons may regulate LMA rhythms. In vivo photometry revealed that while SCNVIP neurons are acutely responsive to light, their activity is otherwise behavioral state invariant. Single-nuclei RNA-sequencing revealed that SCNVIP neurons comprise two transcriptionally distinct subtypes, including putative pacemaker and non-pacemaker populations. Altogether, our work establishes necessity of SCNVIP neurons for the LMA circadian rhythm, elucidates organization of circadian outflow from and modulatory input to SCNVIP cells, and demonstrates a subpopulation-level molecular heterogeneity that suggests distinct functions for specific SCNVIP subtypes.

Role of serotonergic dorsal raphe neurons in hypercapnia-induced arousals.

During obstructive sleep apnea, elevation of CO2 during apneas contributes to awakening and restoring airway patency. We previously found that glutamatergic neurons in the external lateral parabrachial nucleus (PBel) containing calcitonin gene related peptide (PBelCGRP neurons) are critical for causing arousal during hypercapnia. However, others found that genetic deletion of serotonin (5HT) neurons in the brainstem also prevented arousal from hypercapnia. To examine interactions between the two systems, we showed that dorsal raphe (DR) 5HT neurons selectively targeted the PBel. Either genetically directed deletion or acute optogenetic silencing of DRSert neurons dramatically increased the latency of mice to arouse during hypercapnia, as did silencing DRSert terminals in the PBel. This effect was mediated by 5HT2a receptors which are expressed by PBelCGRP neurons. Our results indicate that the serotonergic input from the DR to the PBel via 5HT2a receptors is critical for modulating the sensitivity of the PBelCGRP neurons that cause arousal to rising levels of blood CO2.

Selective activation of serotoninergic dorsal raphe neurons facilitates sleep through anxiolysis.

A role for the brain's serotoninergic (5HT) system in the regulation of sleep and wakefulness has been long suggested. Yet, previous studies employing pharmacological, lesion and genetically driven approaches have produced inconsistent findings, leaving 5HT's role in sleep-wake regulation incompletely understood. Here we sought to define the specific contribution of 5HT neurons within the dorsal raphe nucleus (DRN5HT) to sleep and arousal control. To do this, we employed a chemogenetic strategy to selectively and acutely activate DRN5HT neurons and monitored sleep-wake using electroencephalogram recordings. We additionally assessed indices of anxiety using the open field and elevated plus maze behavioral tests and employed telemetric-based recordings to test effects of acute DRN5HT activation on body temperature and locomotor activity. Our findings indicate that the DRN5HT cell population may not modulate sleep-wake per se, but rather that its activation has apparent anxiolytic properties, suggesting the more nuanced view that DRN5HT neurons are sleep permissive under circumstances that produce anxiety or stress.

An Analysis of Orthopedic Surgical Procedures Performed During U.S. Combat Operations from 2002 to 2016.

INTRODUCTION: Orthopedic surgery constitutes 27% of procedures performed for combat injuries. General surgeons may deploy far forward without orthopedic surgeon support. This study examines the type and volume of orthopedic procedures during 15 years of combat operations in Iraq and Afghanistan. MATERIALS AND METHODS: Retrospective analysis of the US Department of Defense Trauma Registry (DoDTR) was performed for all Role 2 and Role 3 facilities, from January 2002 to May 2016. The 342 ICD-9-CM orthopedic surgical procedure codes identified were stratified into fifteen categories, with upper and lower extremity subgroups. Data analysis used Stata Version 14 (College Station, TX). RESULTS: A total of 51,159 orthopedic procedures were identified. Most (43,611, 85.2%) were reported at Role 3 s. More procedures were reported on lower extremities (21,688, 57.9%). Orthopedic caseload was extremely variable throughout the 15-year study period. CONCLUSIONS: Orthopedic surgical procedures are common on the battlefield. Current dispersed military operations can occur without orthopedic surgeon support; general surgeons therefore become responsible for initial management of all injuries. Debridement of open fracture, fasciotomy, amputation and external fixation account for 2/3 of combat orthopedic volume; these procedures are no longer a significant part of general surgery training, and uncommonly performed by general/trauma surgeons at US hospitals. Given their frequency in war, expertise in orthopedic procedures by military general surgeons is imperative.

Newly identified sleep-wake and circadian circuits as potential therapeutic targets.

Optogenetics and chemogenetics are powerful tools, allowing the specific activation or inhibition of targeted neuronal subpopulations. Application of these techniques to sleep and circadian research has resulted in the unveiling of several neuronal populations that are involved in sleep-wake control, and allowed a comprehensive interrogation of the circuitry through which these nodes are coordinated to orchestrate the sleep-wake cycle. In this review, we discuss six recently described sleep-wake and circadian circuits that show promise as therapeutic targets for sleep medicine. The parafacial zone (PZ) and the ventral tegmental area (VTA) are potential druggable targets for the treatment of insomnia. The brainstem circuit underlying rapid eye movement sleep behavior disorder (RBD) offers new possibilities for treating RBD and neurodegenerative synucleinopathies, whereas the parabrachial nucleus, as a nexus linking arousal state control and breathing, is a promising target for developing treatments for sleep apnea. Therapies that act upon the hypothalamic circuitry underlying the circadian regulation of aggression or the photic regulation of arousal and mood pathway carry enormous potential for helping to reduce the socioeconomic burden of neuropsychiatric and neurodegenerative disorders on society. Intriguingly, the development of chemogenetics as a therapeutic strategy is now well underway and such an approach has the capacity to lead to more focused and less invasive therapies for treating sleep-wake disorders and related comorbidities.

A time to fight: Circadian control of aggression and associated autonomic support.

The central circadian clock, located in the suprachiasmatic nucleus of the mammalian hypothalamus (SCN), regulates daily behavioral rhythms including the temporal propensity for aggressive behavior. Such aggression propensity rhythms are regulated by a functional circuit from the SCN to neurons that drive attack behavior in the ventromedial hypothalamus (VMH), via a relay in the subparaventricular zone (SPZ). In addition to this pathway, the SCN also regulates sleep-wake and locomotor activity rhythms, via the SPZ, in a circuit to the dorsomedial hypothalamus (DMH), a structure that is also known to play a key role in autonomic function and the sympathetic "fight-or-flight" response (which prepares the body for action in stressful situations such as an agonistic encounter). While the autonomic nervous system is known to be under pronounced circadian control, it is less apparent how such autonomic rhythms and their underlying circuitry may support the temporal propensity for aggressive behavior. Additionally, it is unclear how circadian and autonomic dysfunction may contribute to aberrant social and emotional behavior, such as agitation and aggression. Here we review the literature concerning interactions between the circadian and autonomic systems and aggression, and we discuss the implications of these relationships for human neural and behavioral pathologies.

A hypothalamic circuit for the circadian control of aggression.

'Sundowning' in dementia and Alzheimer's disease is characterized by early-evening agitation and aggression. While such periodicity suggests a circadian origin, whether the circadian clock directly regulates aggressive behavior is unknown. We demonstrate that a daily rhythm in aggression propensity in male mice is gated by GABAergic subparaventricular zone (SPZGABA) neurons, the major postsynaptic targets of the central circadian clock, the suprachiasmatic nucleus. Optogenetic mapping revealed that SPZGABA neurons receive input from vasoactive intestinal polypeptide suprachiasmatic nucleus neurons and innervate neurons in the ventrolateral part of the ventromedial hypothalamus (VMH), which is known to regulate aggression. Additionally, VMH-projecting dorsal SPZ neurons are more active during early day than early night, and acute chemogenetic inhibition of SPZGABA transmission phase-dependently increases aggression. Finally, SPZGABA-recipient central VMH neurons directly innervate ventrolateral VMH neurons, and activation of this intra-VMH circuit drove attack behavior. Altogether, we reveal a functional polysynaptic circuit by which the suprachiasmatic nucleus clock regulates aggression.

Inter-domain microbial diversity within the coral holobiont Siderastrea siderea from two depth habitats.

Corals host diverse microbial communities that are involved in acclimatization, pathogen defense, and nutrient cycling. Surveys of coral-associated microbes have been particularly directed toward Symbiodinium and bacteria. However, a holistic understanding of the total microbiome has been hindered by a lack of analyses bridging taxonomically disparate groups. Using high-throughput amplicon sequencing, we simultaneously characterized the Symbiodinium, bacterial, and fungal communities associated with the Caribbean coral Siderastrea siderea collected from two depths (17 and 27 m) on Conch reef in the Florida Keys. S. siderea hosted an exceptionally diverse Symbiodinium community, structured differently between sampled depth habitats. While dominated at 27 m by a Symbiodinium belonging to clade C, at 17 m S. siderea primarily hosted a mixture of clade B types. Most fungal operational taxonomic units were distantly related to available reference sequences, indicating the presence of a high degree of fungal novelty within the S. siderea holobiont and a lack of knowledge on the diversity of fungi on coral reefs. Network analysis showed that co-occurrence patterns in the S. siderea holobiont were prevalent among bacteria, however, also detected between fungi and bacteria. Overall, our data show a drastic shift in the associated Symbiodinium community between depths on Conch Reef, which might indicate that alteration in this community is an important mechanism facilitating local physiological adaptation of the S. siderea holobiont. In contrast, bacterial and fungal communities were not structured differently between depth habitats.

The Use of Telehealth to Teach Reproductive Health to Female Rural High School Students.

STUDY OBJECTIVE: To evaluate the use of telehealth to teach reproductive health to rural areas with high rates of teen pregnancy. DESIGN: Prospective cohort study. SETTING: Two high schools in rural West Virginia. PARTICIPANTS: High school female students who attended telehealth sessions. INTERVENTIONS: Teleconferencing equipment connected rural high schools to a distal academic institution. Telehealth sessions included reproductive health and life skills topics. Demographic information, session pre- and post-tests, and 6- month assessment was obtained. MAIN OUTCOME MEASURES: Reproductive health knowledge, behavior, and self-efficacy were assessed at intervention and at 6 months, along with Likert scale evaluation of telehealth as an educational tool. RESULTS: Fifty-five students participated in the program with an average age of 16.14 (SD 1.24) years. Only 20% (10/50) of subjects' mothers and 12% (6/50) of subjects' fathers had achieved education beyond high school, and 20% (10/50) of subject's mothers had experienced teen pregnancies (age 18 or younger). Sexual activity was reported among 52% (26/50) of subjects, 4/50 (8%) reported desire to become pregnant within the next year, and 4/50 (8%) reported already pregnant. Thirty-seven students completed the 6-month follow-up survey. Reported condom use increased from 20% (10/50) at baseline to 40% (15/37) at 6 months (P = .04) and hormonal contraception use increased from 22% (11/50) to 38% (14/37) (P = .12). Report of human papillomavirus vaccination increased from 38% (10/26) to 70% (26/37) (P = .001) among all subjects. At 6 months, 91.8% (34/37) reported the use of telehealth was "very effective" as a means to teach the material. CONCLUSIONS: Telehealth is an effective tool to teach reproductive health to rural areas.

Slx5/Slx8 Promotes Replication Stress Tolerance by Facilitating Mitotic Progression.

Loss of minichromosome maintenance protein 10 (Mcm10) causes replication stress. We uncovered that S. cerevisiae mcm10-1 mutants rely on the E3 SUMO ligase Mms21 and the SUMO-targeted ubiquitin ligase complex Slx5/8 for survival. Using quantitative mass spectrometry, we identified changes in the SUMO proteome of mcm10-1 mutants and revealed candidates regulated by Slx5/8. Such candidates included subunits of the chromosome passenger complex (CPC), Bir1 and Sli15, known to facilitate spindle assembly checkpoint (SAC) activation. We show here that Slx5 counteracts SAC activation in mcm10-1 mutants under conditions of moderate replication stress. This coincides with the proteasomal degradation of sumoylated Bir1. Importantly, Slx5-dependent mitotic relief was triggered not only by Mcm10 deficiency but also by treatment with low doses of the alkylating drug methyl methanesulfonate. Based on these findings, we propose a model in which Slx5/8 allows for passage through mitosis when replication stress is tolerable.