Astrocytic GABAergic Regulation in Alcohol Use and Major Depressive Disorders.

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS). Most GABAergic neurons synthesize GABA from glutamate and release it in the synaptic cleft in the CNS. However, astrocytes can also synthesize and release GABA, activating GABA receptors in the neighboring neurons in physiological and pathological conditions. As the primary homeostatic glial cells in the brain, astrocytes play a crucial role in regulating GABA homeostasis and synaptic neurotransmission. Accumulating evidence demonstrates that astrocytic GABA dysregulation is implicated in psychiatric disorders, including alcohol use disorder (AUD) and major depressive disorder (MDD), the most prevalent co-occurring psychiatric disorders. Several current medications and emerging pharmacological agents targeting GABA levels are in clinical trials for treating AUD and MDD. This review offers a concise summary of the role of astrocytic GABA regulation in AUD and MDD. We also provide an overview of the current understanding and areas of debate regarding the mechanisms by which astrocytes regulate GABA in the CNS and their potential significance in the molecular basis of AUD and MDD, paving the way toward future research directions and potential therapeutic target areas within this field.

Cortisol levels across the lifespan in common marmosets (Callithrix jacchus).

Human aging is associated with senescence of the hypothalamic-pituitary-adrenal (HPA) axis, leading to progressive dysregulation characterized by increased cortisol exposure. This key hormone is implicated in the pathogenesis of many age-related diseases. Common marmosets (Callithrix jacchus) display a wide spectrum of naturally occurring age-related pathologies that compare similarly to humans and are increasingly used as translational models of aging and age-related disease. Whether the marmoset HPA axis also shows senescence with increasing age is unknown. We analyzed hair cortisol concentration (HCC) across the lifespan of 50 captive common marmosets, ranging in age from approximately 2 months-14.5 years, via a cross-sectional design. Samples were processed and analyzed for cortisol using enzyme immunoassay. HCC ranged from 1416 to 15,343 pg/mg and was negatively correlated with age. We found significant main effects of age group (infant, adolescent, adult, aged, very aged) and sex on HCC, and no interaction effects. Infants had significantly higher levels of HCC compared with all other age groups. Females had higher HCC than males. There was no interaction between age and sex. These results suggest marmosets do not show dysregulation of the HPA axis with increasing age, as measured via HCC.

Serum biomarkers associated with aging and neurodegeneration in common marmosets (Callithrix jacchus).

The common marmoset (Callithrix jacchus), a small South American monkey, is an important nonhuman primate model in the study of aging and age-related neurodegenerative disease, including Alzheimer's disease, Parkinson's disease, and related dementias. Thorough characterization of the wild type marmoset brain agingmodel, including biomarkers of aging and neural degeneration, will further the marmoset's utility in translational research. We measured serum concentration of four key biomarkers of neural degeneration [total tau (T-tau), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and ubiquitin C-terminal hydrolase-L1 (UCH-L1)] via single molecule array from 24 marmosets (female n = 13, male n = 11) ranging in age from 1.3 to 18.7 years. Aged marmosets (>7 years) had significantly higher GFAP, NfL, UCH-L1, and T-tau than adult marmosets. Sex differences were not detected for any of these biomarker concentrations. These data provide an important initial range of reference values for GFAP, NfL, T-tau, and UCH-L1 to evaluate aging and neural health in marmosets, as well as evaluation of therapeutics in clinical models of disease.

Distinct neural mechanisms for heading retrieval and context recognition in the hippocampus during spatial reorientation.

Reorientation, the process of regaining one's bearings after becoming lost, requires identification of a spatial context (context recognition) and recovery of heading direction within that context (heading retrieval). We previously showed that these processes rely on the use of features and geometry, respectively. Here, we examine reorientation behavior in a task that creates contextual ambiguity over a long timescale to demonstrate that mice learn to combine both featural and geometric cues to recover heading with experience. At the neural level, most CA1 neurons persistently align to geometry, and this alignment predicts heading behavior. However, a small subset of cells shows feature-sensitive place field remapping, which serves to predict context. Efficient heading retrieval and context recognition require integration of featural and geometric information in the active network through rate changes. These data illustrate how context recognition and heading retrieval are coded in CA1 and how these processes change with experience.

Determination of dexamethasone dose for cortisol suppression in adult common marmosets (Callithrix jacchus).

We conducted a dose-response study of dexamethasone to investigate an optimal dexamethasone suppression test for common marmosets. Twelve marmosets received 0.1, 0.5, or 1.0 mg/kg dexamethasone. Doses of 0.5 and 1.0 mg/kg both suppressed endogenous cortisol for at least 18 h with greater individual variability in the lower 0.5 mg/kg dose.

Navigable Space and Traversable Edges Differentially Influence Reorientation in Sighted and Blind Mice.

Reorientation enables navigators to regain their bearings after becoming lost. Disoriented individuals primarily reorient themselves using the geometry of a layout, even when other informative cues, such as landmarks, are present. Yet the specific strategies that animals use to determine geometry are unclear. Moreover, because vision allows subjects to rapidly form precise representations of objects and background, it is unknown whether it has a deterministic role in the use of geometry. In this study, we tested sighted and congenitally blind mice (Ns = 8-11) in various settings in which global shape parameters were manipulated. Results indicated that the navigational affordances of the context-the traversable space-promote sampling of boundaries, which determines the effective use of geometric strategies in both sighted and blind mice. However, blind animals can also effectively reorient themselves using 3D edges by extensively patrolling the borders, even when the traversable space is not limited by these boundaries.

Delays to Reward Delivery Enhance the Preference for an Initially Less Desirable Option: Role for the Basolateral Amygdala and Retrosplenial Cortex.

Temporal costs influence reward-based decisions. This is commonly studied in temporal discounting tasks that involve choosing between cues signaling an imminent reward option or a delayed reward option. However, it is unclear whether the temporal delay before a reward can alter the value of that option. To address this, we identified the relative preference between different flavored rewards during a free-feeding test using male and female rats. Animals underwent training where either the initial preferred or the initial less preferred reward was delivered noncontingently. By manipulating the intertrial interval during training sessions, we could determine whether temporal delays impact reward preference in a subsequent free-feeding test. Rats maintained their initial preference if the same delays were used across all training sessions. When the initial less preferred option was delivered after short delays (high reward rate) and the initial preferred option was delivered after long delays (low reward rate), rats expectedly increased their preference for the initial less desirable option. However, rats also increased their preference for the initial less desirable option under the opposite training contingencies: delivering the initial less preferred reward after long delays and the initial preferred reward after short delays. These data suggest that sunk temporal costs enhance the preference for a less desirable reward option. Pharmacological and lesion experiments were performed to identify the neural systems responsible for this behavioral phenomenon. Our findings demonstrate the basolateral amygdala and retrosplenial cortex are required for temporal delays to enhance the preference for an initially less desirable reward.SIGNIFICANCE STATEMENT The goal of this study was to determine how temporal delays influence reward preference. We demonstrate that delivering an initially less desirable reward after long delays subsequently increases the consumption and preference for that reward. Furthermore, we identified the basolateral amygdala and the retrosplenial cortex as essential nuclei for mediating the change in reward preference elicited by sunk temporal costs.

Differential effect of sleep deprivation on place cell representations, sleep architecture, and memory in young and old mice.

Poor sleep quality is associated with age-related cognitive decline, and whether reversal of these alterations is possible is unknown. In this study, we report how sleep deprivation (SD) affects hippocampal representations, sleep patterns, and memory in young and old mice. After training in a hippocampus-dependent object-place recognition (OPR) task, control animals sleep ad libitum, although experimental animals undergo 5 h of SD, followed by recovery sleep. Young controls and old SD mice exhibit successful OPR memory, whereas young SD and old control mice are impaired. Successful performance is associated with two cellular phenotypes: (1) "context" cells, which remain stable throughout training and testing, and (2) "object configuration" cells, which remap when objects are introduced to the context and during testing. Additionally, effective memory correlates with spindle counts during non-rapid eye movement (NREM)/rapid eye movement (REM) sigma transitions. These results suggest SD may serve to ameliorate age-related memory deficits and allow hippocampal representations to adapt to changing environments.

CLINICAL DECISION MAKING AND DIFFERENTIAL DIAGNOSIS IN A CYCLIST WITH UPPER QUARTER PAIN, NUMBNESS, AND WEAKNESS: A CASE REPORT.

BACKGROUND AND PURPOSE: Differentiating between cervical nerve root and peripheral nerve injuries can be challenging. A phenomenon known as double crush syndrome may increase the susceptibility to injury and symptoms at other locations along the course of the nerve. The purpose of this case report is to describe the physical therapy differential diagnosis and management of a cyclist with upper extremity pain, weakness, and paresthesia. CASE DESCRIPTION: The subject was referred to physical therapy with a diagnosis of cervical disc disease. His chief complaints were chronic neck and right shoulder pain as well as a recent onset of right hand numbness and weakness following 100-mile bike ride one month prior. Diagnostic imaging revealed multi-level degenerative changes of the cervical spine. Initial electromyography and nerve conduction studies (EMG/NCS) indicated right ulnar neuropathy at the elbow. The ultimate incorporation of ulnar nerve mobilizations in various positions immediately decreased symptoms. In light of the subject's improvement after ulnar nerve mobilizations, imaging findings, and EMG/NCS findings, the subject's presentation was consistent with a double crush syndrome with C8 nerve root compression and distal ulnar nerve compression at the elbow. OUTCOMES: The subject demonstrated full resolution of all symptoms, 0% disability on the Neck Disability Index, 8.3% disability of the Disabilities of the Arm, Shoulder, and Hand questionnaire, normal EMG/NCV findings, and unrestricted return to work and endurance cycling at three months and maintained at one year. He did not require hand surgery. DISCUSSION: This case report highlights the importance of continual clinical re-examination and re-assessment with ancillary diagnostic testing, especially if chosen interventions are not eliciting desired responses. The identification of key risk factors, such as occupation and recreational activities is imperative in achieving the most efficacious clinical treatment. In this case, the recognition of a double crush syndrome assisted in optimizing the physical therapy plan of care and the subject ultimately achieving full recovery. LEVEL OF EVIDENCE: Level 4.

Calculating the Position of the Joint Line of the Knee Using Anatomical Landmarks.

Restoration of the joint line of the knee during primary and revision total knee arthroplasty is a step that directly influences patient outcomes. In revision total knee arthroplasty, necessary bony landmarks may be missing or obscured, so there remains a lack of consensus on how to accurately identify and restore the joint line of the knee. In this study, 50 magnetic resonance images of normal knees were analyzed to determine a quantitative relationship between the joint line of the knee and 6 bony landmarks: medial and lateral femoral epicondyles, medial and lateral femoral metaphyseal flares, tibial tubercle, and proximal tibio-fibular joint. Wide variability was found in the absolute distance from each landmark to the joint line of the knee, including significant differences between the sexes. Normalization of the absolute distances to femoral or tibial diameters revealed reliable spatial relationships to the joint line of the knee. The joint line was found to be equidistant from the lateral femoral epicondyle and the proximal tibio-fibular joint, representing a reproducible point of reference for joint line restoration. The authors propose a simple 3-step algorithm that can be used with magnetic resonance imaging, computed tomography, or radiography to reliably determine the anatomical location of the joint line of the knee relative to the surrounding bony anatomy. [Orthopedics. 2016; 39(6):381-386.].

Giant cell tumor of bone.

EDUCATIONAL OBJECTIVES As a result of reading this article, physicians should be able to: 1. Identify at-risk populations for giant cell tumor of bone. 2. Recognize the biology that drives giant cell tumor of bone. 3. Describe modern surgical and adjuvant techniques to effectively treat giant cell tumor of bone. 4. Recognize the complications associated with radiation therapy, poor resection, and adjuvant treatments. Giant cell tumor of bone (GCT) is a benign, locally aggressive bone tumor. Giant cell tumor of bone primarily affects the young adult patient population. The natural history of GCT is progressive bone destruction leading to joint deformity and disability. Surgery is the primary mode of treatment, but GCT has a tendency to recur locally despite a range of adjuvant surgical options. Pulmonary metastasis has been described. However, systemic spread of GCT rarely becomes progressive, leading to death. This review presents the clinicopathologic features of GCT and a historical perspective that highlights the current rationale and controversies regarding the treatment of GCT.

Perforated tubular duodenal duplication in a 79 year old woman: Case report and review of the literature.

INTRODUCTION: Enteric duplications are rare congenital anomalies of the digestive tract that can occur anywhere along its length, with the majority being found in the small intestine. The duodenum is the least common site. Almost all symptomatic duodenal duplications present early in life with abdominal pain and pancreatitis. To the best of our knowledge this is the first described case of a perforated tubular duodenal duplication in an elderly adult. PRESENTATION OF CASE: We present a case of a perforated tubular duodenal duplication in an elderly woman. She presented with diffuse abdominal pain, fever, and tachycardia. Emergent exploratory laparotomy revealed a perforated duodenal duplication. Excision of the duodenal duplication and primary closure of the defect was performed successfully. The patient recovered well. DISCUSSION: Enteric duplications are poorly understood anomalies of embryonic development. They can be cystic or tubular dorsal enteric remnants lying in communication with the alimentary tract that are distinct from diverticula. A tubular duodenal duplication is exceedingly rare, and this case is made even more notable in that such an anomaly presented with sepsis and occurred in a 79 year old woman. We are unsure why the duplication ruptured. To the best of our knowledge this case represents the first report of a ruptured tubular duodenal duplication in an elderly adult. CONCLUSION: This is a very rare occurrence and has never been described in an elderly patient before. Excision and primary closure led to a good outcome.

Case report: artificial elevation of prothrombin time by telavancin.

BACKGROUND: Methicillin-resistant Staphylococcus aureus infections are a well-documented risk of surgery and are becoming increasingly difficult to treat owing to continued acquired resistance. A new antibiotic for treatment of Staphylococcus aureus is telavancin. CASE DESCRIPTION: A patient at our institution was prescribed telavancin for multiple spinal abscesses before spinal surgery. Routine preoperative testing revealed an international normalized ratio (INR) of 2.05 with no clear cause. Careful review of the patient's medication history and prescriber information revealed that telavancin may interfere with prothrombin time (PT/INR) testing. In vitro testing by our laboratory confirmed an association between telavancin dose and an increase in PT/INR. An alternative reagent for PT/INR testing unaffected by telavancin dose revealed a PT/INR of 0.97. LITERATURE REVIEW: Telavancin interacts with artificial phospholipid surfaces used to monitor coagulation while having no actual effect on coagulation. PURPOSES AND CLINICAL RELEVANCE: All physicians, especially orthopaedic surgeons, should be aware of the effects of telavancin and ensure proper measures are taken to acquire the true INR by switching the reagent used to test PT/INR or ensuring the PT/INR is drawn before telavancin dosing.

Ablation of rat TRPV1-expressing Adelta/C-fibers with resiniferatoxin: analysis of withdrawal behaviors, recovery of function and molecular correlates.

BACKGROUND: Ablation of TRPV1-expressing nociceptive fibers with the potent capsaicin analog resiniferatoxin (RTX) results in long lasting pain relief. RTX is particularly adaptable to focal application, and the induced chemical axonopathy leads to analgesia with a duration that is influenced by dose, route of administration, and the rate of fiber regeneration. TRPV1 is expressed in a subpopulation of unmyelinated C- and lightly myelinated Adelta fibers that detect changes in skin temperature at low and high rates of noxious heating, respectively. Here we investigate fiber-type specific behaviors, their time course of recovery and molecular correlates of axon damage and nociception using infrared laser stimuli following an RTX-induced peripheral axonopathy. RESULTS: RTX was injected into rat hind paws (mid-plantar) to produce thermal hypoalgesia. An infrared diode laser was used to stimulate Adelta fibers in the paw with a small-diameter (1.6 mm), high-energy, 100 msec pulse, or C-fibers with a wide-diameter (5 mm), long-duration, low-energy pulse. We monitored behavioral responses to indicate loss and regeneration of fibers. At the site of injection, responses to C-fiber stimuli were significantly attenuated for two weeks after 5 or 50 ng RTX. Responses to Adelta stimuli were significantly attenuated for two weeks at the highest intensity stimulus, and for 5 weeks to a less intense Adelta stimulus. Stimulation on the toe, a site distal to the injection, showed significant attenuation of Adelta responses for 7- 8 weeks after 5 ng, or 9-10 weeks after 50 ng RTX. In contrast, responses to C-fiber stimuli exhibited basically normal responses at 5 weeks after RTX. During the period of fiber loss and recovery, molecular markers for nerve regeneration (ATF3 and galanin) are upregulated in the dorsal root ganglia (DRG) when behavior is maximally attenuated, but markers of nociceptive activity (c-Fos in spinal cord and MCP-1 in DRG), although induced immediately after RTX treatment, returned to normal. CONCLUSION: Behavioral recovery following peripheral RTX treatment is linked to regeneration of TRPV1-expressing Adelta and C-fibers and sustained expression of molecular markers. Infrared laser stimulation is a potentially valuable tool for evaluating the behavioral role of Adelta fibers in pain and pain control.