Improving Bone Health in Patients with Metastatic Prostate Cancer with the Use of Algorithm-Based Clinical Practice Tool.

Background: The bone health of patients with locally advanced and metastatic prostate cancer is at risk from treatment-related bone density loss and skeletal-related events from metastatic disease in bones. Evidence-based guidelines recommend using denosumab or zoledronic acid at bone metastasis-indicated dosages in the setting of castration-resistant prostate cancer with bone metastases and at the osteoporosis-indicated dosages in the hormone-sensitive setting in patients with a significant risk of fragility fracture. For the concerns of jaw osteonecrosis, a dental evaluation is recommended before starting bone-modifying agents. The literature review suggests a limited evidence-based practice for bone health with prostate cancer in the real world. Both under-treatment and inappropriate dosing of bone remodeling therapies place additional risks to bone health. An incomplete dental work up before starting bone-modifying agents increases the risk of jaw osteonecrosis. Methods: We created an algorithm-based clinical practice tool to minimize the deviation from evidence-based guidelines at our center and provide appropriate bone health care to our patients by ensuring indication-appropriate dosing and dental screening rates. This order set was incorporated into the electronic medical record system for ordering a bone remodeling agent for prostate cancer. The tool prompts the clinicians to follow the appropriate algorithm in a stepwise manner to ensure a pretreatment dental evaluation and use of the correct dosage of drugs. Results: We analyzed the data from Sept 2019 to April 2022 following the incorporation of this tool. 0/35 (0%) patients were placed on inappropriate bone modifying agent dosing, and dental health was addressed in every patient before initiating treatment. We compared the change in the practice of prescribing and noted a significant difference in the clinician's practice while prescribing denosumab/zoledronic acid before and after implementation of this tool [incorrect dosing: 24/41 vs. 0/35 (p < 0.00001)]; and an improvement in pretreatment dental checkup before and after implementation of the tool was noted to be [missed dental evaluation:12/41 vs. 0/35 (p < 0.00001)]. Conclusion: We found that incorporating an evidence-based algorithm in the order set while prescribing bone remodeling agents significantly improved our institutional clinical practice of indication-appropriate dosing and dental screening rates, and facilitated high-quality, evidence-based care to our patients with prostate cancer.

Bone Health in Patients With Prostate Cancer: An Evidence-Based Algorithm.

BACKGROUND: The veteran population has an increasingly high number of patients who have either survived, are currently living with, or are being treated for prostate cancer. Survivorship concerns related to the treatment of this disease is a relevant topic in the Veterans Health Administration, given the longevity of life with localized disease treatment and the fairly durable therapies for metastatic disease. Long-term androgen deprivation therapy (ADT) forms the backbone of treatment for advanced and metastatic castration-sensitive prostate cancer. OBSERVATIONS: The potential bone-health complications resulting from treatment with ADT should be recognized as many patients live for prolonged periods with stable or controlled disease. It is well established that prolonged ADT can lead to significant bone loss and increased fracture risk, which increases all-cause mortality and disability. Bone-remodeling agents, such as bisphosphonates and receptor-activated nuclear factor κ-B ligand inhibitors, are recommended to reduce the risk of fragility fractures in patients at high risk due to diminished bone density while on hormone deprivation therapy for hormone-naive prostate cancer. These agents are also indicated at a higher dose to prevent complications from bone metastases in castration-resistant prostate cancer with bone metastases. CONCLUSIONS: This article reviews recent studies on bone health in men with prostate cancer and presents an evidence-based algorithm for bone-health monitoring during treatment and recommended interventions.

Nivolumab-induced hypothyoidism with consequent hypothyroid related myopathy.

PURPOSE: Nivolumab is a fully human IgG4 programmed death 1 immune checkpoint inhibitor (ICI) antibody that has anti-tumor activity by selectively blocking the interaction of the programmed death 1 receptor with its two known programmed death ligands PD-L1 and PD-L2. In doing so, this immune checkpoint inhibitor removes the negative signal stifling T cell activation and proliferation within the tumor microenvironment and demonstrates favorable antitumor activity. CASE REPORT: We report an interesting case of immune checkpoint inhibitor-induced primary hypothyroidism with associated hypothyroid myopathy in a young patient with surgically resected stage IIIB melanoma receiving adjuvant nivolumab. He presented 12 weeks into therapy with severe myalgias, arthralgias, and intermittent disequilibrium of unclear etiology. Laboratory evaluation demonstrated a significant elevation in thyroid stimulating hormone and creatine kinase with an undetectable free T4 with standard laboratory measurement. With thyroid hormone replacement therapy alone, he had rapid improvement in his musculoskeletal symptoms and laboratory parameters over a three-week period. DISCUSSION: This case emphasizes the serious nature of endocrine immune-related adverse events in patients receiving immune checkpoint inhibitors. Additionally, it highlights that unlike most other immune-related adverse events, endocrine immune-related adverse events can generally be managed with adequate hormone replacement alone with swift improvements in symptoms. This allows patients to continue immune checkpoint inhibitors safely without immunosuppression which may dampen the anti-tumor activity of these agents. CONCLUSION: This case highlights the importance of early recognition and the appropriate management of endocrine immune-related adverse events to maximize patient safety and good outcomes.

The D-dimer assay.

D-dimer is an indirect marker of fibrinolysis and fibrin turnover; this molecule exhibits unique properties as a biological marker of hemostatic abnormalities as well as an indicator of intravascular thrombosis. D-dimer is a soluble fibrin degradation product that results from the systematic degradation of vascular thrombi through the fibrinolytic mechanism. Because of this, the D-dimer serves as a valuable marker of activation of coagulation and fibrinolysis in a number of clinical scenarios. Most commonly, D-dimer has been extensively investigated for excluding the diagnosis of venous thromboembolism (VTE) and is used routinely for this indication. In addition, D-dimer has been evaluated for determining the optimal duration of anticoagulation in VTE patients, for diagnosing and monitoring disseminated intravascular coagulation, and for monitoring other conditions in which the patient is at high risk of bleeding or thrombosis. Limitations of the assay include D-dimer elevation in a constellation of clinical scenarios (age, pregnancy, and cancer) and lack of clinical standardization.

Individual differences in conflict detection during reasoning.

Decades of reasoning and decision-making research have established that human judgment is often biased by intuitive heuristics. Recent "error" or bias detection studies have focused on reasoners' abilities to detect whether their heuristic answer conflicts with logical or probabilistic principles. A key open question is whether there are individual differences in this bias detection efficiency. Here we present three studies in which co-registration of different error detection measures (confidence, response time and confidence response time) allowed us to assess bias detection sensitivity at the individual participant level in a range of reasoning tasks. The results indicate that although most individuals show robust bias detection, as indexed by increased latencies and decreased confidence, there is a subgroup of reasoners who consistently fail to do so. We discuss theoretical and practical implications for the field.

Primary Cystic Pleuropulmonary Synovial Sarcoma Presenting as Recurrent Pneumothorax.

Primary pleuropulmonary synovial sarcomas are quite rare, representing 0.1-0.5% of all pulmonary malignancies. We report an entirely cystic monophasic synovial sarcoma in a 25-year-old male who presented with recurrent pneumothorax and no evidence of a mass lesion on imaging. The purpose of this case report is to increase awareness of neoplasms clinically presenting as a pneumothorax with no imagining evidence of a mass-forming lesion and emphasize the significance of fluorescent in situ hybridization testing in nontypical synovial sarcoma cases.

Structural mapping in statistical word problems: A relational reasoning approach to Bayesian inference.

Presenting natural frequencies facilitates Bayesian inferences relative to using percentages. Nevertheless, many people, including highly educated and skilled reasoners, still fail to provide Bayesian responses to these computationally simple problems. We show that the complexity of relational reasoning (e.g., the structural mapping between the presented and requested relations) can help explain the remaining difficulties. With a non-Bayesian inference that required identical arithmetic but afforded a more direct structural mapping, performance was universally high. Furthermore, reducing the relational demands of the task through questions that directed reasoners to use the presented statistics, as compared with questions that prompted the representation of a second, similar sample, also significantly improved reasoning. Distinct error patterns were also observed between these presented- and similar-sample scenarios, which suggested differences in relational-reasoning strategies. On the other hand, while higher numeracy was associated with better Bayesian reasoning, higher-numerate reasoners were not immune to the relational complexity of the task. Together, these findings validate the relational-reasoning view of Bayesian problem solving and highlight the importance of considering not only the presented task structure, but also the complexity of the structural alignment between the presented and requested relations.

The Doubting System 1: Evidence for automatic substitution sensitivity.

A long prevailing view of human reasoning suggests severe limits on our ability to adhere to simple logical or mathematical prescriptions. A key position assumes these failures arise from insufficient monitoring of rapidly produced intuitions. These faulty intuitions are thought to arise from a proposed substitution process, by which reasoners unknowingly interpret more difficult questions as easier ones. Recent work, however, suggests that reasoners are not blind to this substitution process, but in fact detect that their erroneous responses are not warranted. Using the popular bat-and-ball problem, we investigated whether this substitution sensitivity arises out of an automatic System 1 process or whether it depends on the operation of an executive resource demanding System 2 process. Results showed that accuracy on the bat-and-ball problem clearly declined under cognitive load. However, both reduced response confidence and increased response latencies indicated that biased reasoners remained sensitive to their faulty responses under load. Results suggest that a crucial substitution monitoring process is not only successfully engaged, but that it automatically operates as an autonomous System 1 process. By signaling its doubt along with a biased intuition, it appears System 1 is "smarter" than traditionally assumed.

Malignant Phyllodes Tumor Presenting in Bone, Brain, Lungs, and Lymph Nodes.

INTRODUCTION: Phyllodes tumors (PTs) are rare fibroepithelial tumors of the breast which are classified as benign, borderline, or malignant. Malignant PTs account for <1% of malignant breast tumors, and borderline tumors have potential to progress to malignant tumors. Metastatic recurrences are most commonly documented in bone and lungs. We report an extremely rare presentation of recurrent malignant PTs involving the brain, lung, lymph nodes, and bone. CASE: A 66-year-old female presented with a large breast mass. Biopsy identified malignant PT, treated by mastectomy. One year later she presented with acute back pain; imaging showed pathological L4 spinal compression fracture. Core biopsy confirmed PT. Staging identified additional metastases in the lymph nodes, brain, and lung. DISCUSSION: PTs are rare and fast-growing tumors that originate from periductal stromal tissues and are composed of both epithelial and stromal components. Histologically, they are classified as benign, borderline, or malignant. The prognosis of the malignant type is poorly defined, with local recurrence occurring in 10-40% and metastases in 10%. Chemotherapy and radiotherapy are generally ineffective in this tumor type. The most common metastatic sites for malignant cases are the lung and bones, but in rare instances, PTs may metastasize elsewhere. CONCLUSION: We report a rare presentation of recurrent malignant PT presenting as pathological fracture of the lumbar spine with impingement on the spinal column, along with cerebellar, nodal, and pulmonary metastases. Only 1 similar case has been previously reported.

Comprehension and computation in Bayesian problem solving.

Humans have long been characterized as poor probabilistic reasoners when presented with explicit numerical information. Bayesian word problems provide a well-known example of this, where even highly educated and cognitively skilled individuals fail to adhere to mathematical norms. It is widely agreed that natural frequencies can facilitate Bayesian inferences relative to normalized formats (e.g., probabilities, percentages), both by clarifying logical set-subset relations and by simplifying numerical calculations. Nevertheless, between-study performance on "transparent" Bayesian problems varies widely, and generally remains rather unimpressive. We suggest there has been an over-focus on this representational facilitator (i.e., transparent problem structures) at the expense of the specific logical and numerical processing requirements and the corresponding individual abilities and skills necessary for providing Bayesian-like output given specific verbal and numerical input. We further suggest that understanding this task-individual pair could benefit from considerations from the literature on mathematical cognition, which emphasizes text comprehension and problem solving, along with contributions of online executive working memory, metacognitive regulation, and relevant stored knowledge and skills. We conclude by offering avenues for future research aimed at identifying the stages in problem solving at which correct vs. incorrect reasoners depart, and how individual differences might influence this time point.

Reasoning and choice in the Monty Hall Dilemma (MHD): implications for improving Bayesian reasoning.

The Monty Hall Dilemma (MHD) is a two-step decision problem involving counterintuitive conditional probabilities. The first choice is made among three equally probable options, whereas the second choice takes place after the elimination of one of the non-selected options which does not hide the prize. Differing from most Bayesian problems, statistical information in the MHD has to be inferred, either by learning outcome probabilities or by reasoning from the presented sequence of events. This often leads to suboptimal decisions and erroneous probability judgments. Specifically, decision makers commonly develop a wrong intuition that final probabilities are equally distributed, together with a preference for their first choice. Several studies have shown that repeated practice enhances sensitivity to the different reward probabilities, but does not facilitate correct Bayesian reasoning. However, modest improvements in probability judgments have been observed after guided explanations. To explain these dissociations, the present review focuses on two types of causes producing the observed biases: Emotional-based choice biases and cognitive limitations in understanding probabilistic information. Among the latter, we identify a crucial cause for the universal difficulty in overcoming the equiprobability illusion: Incomplete representation of prior and conditional probabilities. We conclude that repeated practice and/or high incentives can be effective for overcoming choice biases, but promoting an adequate partitioning of possibilities seems to be necessary for overcoming cognitive illusions and improving Bayesian reasoning.

Screening ancient tuberculosis with qPCR: challenges and opportunities.

The field of ancient DNA (aDNA) has rapidly accelerated in recent years as a result of new methods in next-generation sequencing, library preparation and targeted enrichment. Such research is restricted, however, by the highly variable DNA preservation within different tissues, especially when isolating ancient pathogens from human remains. Identifying positive candidate samples via quantitative PCR (qPCR) for downstream procedures can reduce reagent costs, increase capture efficiency and maximize the number of sequencing reads of the target. This study uses four qPCR assays designed to target regions within the Mycobacterium tuberculosis complex (MTBC) to examine 133 human skeletal samples from a wide geographical and temporal range, identified by the presence of skeletal lesions typical of chronic disseminated tuberculosis. Given the inherent challenges working with ancient mycobacteria, strict criteria must be used and primer/probe design continually re-evaluated as new data from bacteria become available. Seven samples tested positive for multiple MTBC loci, supporting them as strong candidates for downstream analyses. Using strict and conservative criteria, qPCR remains a fast and effective screening tool when compared with screening by more expensive sequencing and enrichment technologies.

Integrating human health and environmental health into the DPSIR framework: a tool to identify research opportunities for sustainable and healthy communities.

The U.S. Environmental Protection Agency has recently realigned its research enterprise around the concept of sustainability. Scientists from across multiple disciplines have a role to play in contributing the information, methods, and tools needed to more fully understand the long-term impacts of decisions on the social and economic sustainability of communities. Success will depend on a shift in thinking to integrate, organize, and prioritize research within a systems context. We used the Driving forces-Pressures-State-Impact-Response (DPSIR) framework as a basis for integrating social, cultural, and economic aspects of environmental and human health into a single framework. To make the framework broadly applicable to sustainability research planning, we provide a hierarchical system of DPSIR keywords and guidelines for use as a communication tool. The applicability of the integrated framework was first tested on a public health issue (asthma disparities) for purposes of discussion. We then applied the framework at a science planning meeting to identify opportunities for sustainable and healthy communities research. We conclude that an integrated systems framework has many potential roles in science planning, including identifying key issues, visualizing interactions within the system, identifying research gaps, organizing information, developing computational models, and identifying indicators.

Crux vena cava filter.

Inferior vena cava filters are widely accepted for pulmonary embolic prophylaxis in high-risk patients with contraindications to anticoagulation. While long-term complications have been associated with permanent filters, retrievable filters are now available and have resulted in the rapid expansion of this technology. Nonetheless, complications are still reported with optional filters. Furthermore, device tilting and thrombus load may prevent retrieval in up to 30% of patients, thereby eliminating the benefits of this technology. The Crux vena cava filter is a novel, self-centering, low-profile filter that is designed for ease of delivery, retrievability and improved efficacy while limiting fatigue-related device complications. This device has been proven safe and user-friendly in an ovine model and has recently been implanted in human subjects.

Evaluation of the Crux IVC Filter in an animal model.

PURPOSE: To determine the safety and performance of a new inferior vena cava (IVC) filter in an ovine model and evaluate the retrievability at 5 weeks. METHODS: The Crux Vena Cava Filter (VCF) is composed of 2 nitinol spiral supports with a polymeric filter suspended between them. Retrieval tails on each end facilitate retrieval. Twelve filters were placed in the infrarenal IVCs of 12 sheep. The vessels were imaged pre and post deployment to assess acute device performance. At 5 weeks, the vessels were re-imaged to evaluate continued device performance and vessel integrity. Nine of 12 filters were retrieved, and the animals were returned to their housing. The other 3 animals were sacrificed, and the filters and vessels were processed for gross and histological examination. At 9 weeks, 4 weeks after filter retrieval, vessel integrity of the remaining 9 animals was again assessed under fluoroscopy. The animals were sacrificed, and the IVCs were explanted for study. RESULTS: All 12 filters were implanted without complications at the intended deployment site and remained fixed over the implantation period. At 5 weeks, the filters intended for recovery were successfully retrieved, with a mean capture time of 9.6+/-13.7 minutes. There were no complications during the 4-week follow-up after filter retrieval. Post-retrieval imaging at 5 and 9 weeks showed no visible signs of vessel wall damage. Histological study of 3 explanted vessels and filters revealed slight neointima encapsulation of the filter elements and minimal incorporation. Gross examination of the post-retrieval vessel walls after the 4-week healing period showed minimal superficial vessel damage; histology showed minimal residual signs of hemorrhage, with little to no inflammatory reaction. CONCLUSION: The Crux VCF was deployed and safely retrieved without incident at 5 weeks in an animal model. There was no significant damage seen to the IVCs 1 month after filter retrieval.

Evaluation of wall motion and dynamic geometry of the inferior vena cava using intravascular ultrasound: implications for future device design.

PURPOSE: To use intravascular ultrasound (IVUS) to define the wall motion of the inferior vena cava (IVC) during normal respiratory cycles and evaluate its dynamic geometry during Valsalva maneuvers. METHODS: Between September 2005 and October 2006, 10 patients who were having IVC filters placed underwent IVUS prior to filter implantation. With the anesthetized patient in a supine position, a 10-second IVUS recording of IVC motion below the renal veins was made during both normal respiratory cycles and Valsalva maneuvers. Diameters (n = 100 measurements) were measured from the epicenter of the lumen in both a long and short axis. Changes in diameters were evaluated using a Student t test for paired data; variations in IVC wall motion circumference of the vessel were compared using an analysis of variance for repeated measurements. Intra-/interobserver variability was analyzed with Bland-Altman plots. RESULTS: The mean IVC diameter was 14.3+/-4.1 mm in the short axis and 23.2+/-3.5 mm in the long axis. There was significant variation in infrarenal IVC wall movement about the circumference, with 1.4+/-0.2 mm (range 0.6-1.8) displacement in the short axis and 1.0+/-0.2 mm (range 0.2-1.4) displacement in the long axis during the normal respiratory cycle (p = 0.04). In the short axis, the IVC diameter significantly increased with Valsalva from 14.3+/-4.1 to 19.6+/-1.2 mm (p = 0.0001); in the long axis, the diameter increased from 23.2+/-3.5 to 24+/-1.2 mm (p = 0.02). With Valsalva, there was a significantly greater change in the short axis (30.9%+/-4.8%) compared to the long axis (3.4%+/-2.2%; p = 0.0001). There were no significant differences in the interobserver and intraobserver measurements. CONCLUSION: In the supine position, the IVC is elliptical and deforms anisotropically during the normal respiratory cycle. The greatest displacement (36%) is in the short axis during a Valsalva maneuver. These profound changes within the venous system will require intracaval devices to have active fixation to prevent migration. Devices should be designed to accommodate these changes to prevent fatigue failure.

Dynamic geometry and wall thickness of the aortic neck of abdominal aortic aneurysms with intravascular ultrasonography.

BACKGROUND: It is commonly assumed that the aortic wall deforms uniformly and has uniform wall thickness about the circumference. The purpose of this study was to evaluate the aortic wall motion and thickness in the infrarenal aortic neck of patients with abdominal aortic aneurysms who were undergoing endovascular repair (EVAR) and to compare the dynamic measurements of intravascular ultrasonography with the static measurements of computed tomographic angiography (CTA). METHODS: A total of 25 patients were evaluated before surgery with CTA and three-dimensional reconstructions on a Vitrea workstation, followed by intraoperative assessment of the proximal aortic neck with intravascular ultrasonography (IVUS) before EVAR. Infrarenal aortic neck dimensions on CTA were obtained at 1-mm intervals, but for the purposes of this study all dimensions on CTA were obtained 1 cm below the lowest renal artery. IVUS analysis of the proximal aortic neck was obtained with a 10-second recorded data loop of aortic wall motion. A Digital Imaging and Communications in Medicine viewer was used to view the recorded loop of aortic movement, and each image was captured and then evaluated with a SCION PCI Frame Grabber to determine aortic dimensions and wall thickness. IVUS diameters (250 measurements of each aorta) were recorded through a full continuous cardiac cycle from the epicenter of the lumen (maintaining the left renal vein in its normal anatomic configuration) in an anteroposterior (AP) direction in the area of greatest wall movement and 90 degrees perpendicular to this direction (lateral movement). RESULTS: There was significant variation in infrarenal aortic wall movement about the circumference, with 1.7 +/- 0.6 mm (range, 0.6-2.7 mm) displacement in the AP direction and 0.9 +/- 0.5 mm (range, 0.3-1.5 mm) displacement in the lateral direction (P < .001). Aortic wall thickness was greater in the region of increased AP wall motion than in the area of lesser lateral wall motion (2.3 +/- 0.6 mm vs 1.2 +/- 0.3 mm; P < .001). There was no difference between the IVUS and CTA aortic neck measurements (25.5 vs 25.6 mm; not significant) during the midpoint of the cardiac cycle of IVUS. However, at peak systole, IVUS recorded a greater diameter than CTA (26.4 vs 25.6 mm; P < .001), and at end-diastole, IVUS recorded a smaller diameter than CTA (24.7 vs 25.6 mm; P = .01). CONCLUSIONS: The infrarenal neck of aortic aneurysms deforms anisotropically during the cardiac cycle. The greatest displacement is in the AP direction and corresponds with a significantly greater wall thickness in this area. The magnitude of cyclic change in aortic diameter can be as high as 11%. Further evaluation of proximal aortic neck wall motion after EVAR is warranted to determine the interaction of various stent designs and the aortic wall.

Device-specific resistance to in vivo displacement of stent-grafts implanted with maximum iliac fixation.

PURPOSE: To compare the in vivo device-specific downward displacement force of various externally supported endografts implanted with maximum iliac fixation. METHODS: Twenty female sheep had aneurysms created with a graft patch in the infrarenal aorta. In 12 animals, a fully supported modular bifurcated stent-graft [AneuRx (n=4), Talent (n=4), or Zenith (n=4)] was deployed; in the other 8, a bifurcated aortic graft was surgically anastomosed to the infrarenal aorta. All grafts were displaced in vivo by applying downward traction to a guidewire brought out both femoral arteries. The peak force to cause initial stent-graft migration or disruption of the sutured anastomosis was recorded and compared. RESULTS: There was no difference in animal size, aortic neck diameter or length, aneurysm size, or iliac artery diameter for animals receiving the AneuRx, Talent, or Zenith stent-grafts and those undergoing surgical repair. The mean length of iliac fixation was 31.0+/-0.3 mm, 30.8+/-0.5 mm, and 31.3+/-0.6 mm for the AneuRx, Talent, and Zenith devices, respectively (p=NS). Peak force to initiate migration was 30.2+/-5.5 N (range 25-38) for the AneuRx, 44.8+/-5.6 N (range 40-53) for the Talent, 46.7+/-5.4 N (range 38-55) for the Zenith, and 40.6+/-7.5 N (range 31-50) for the surgical anastomosis (p=0.01). There was no difference detected in the peak force to initiate migration between the suprarenally affixed Talent and Zenith stent-grafts and the surgical anastomosis (p=0.55). CONCLUSION: Devices with a suprarenal component require significantly greater force to cause downward displacement compared to infrarenal devices. The force required to displace a suprarenal device with maximal iliac fixation was equivalent to the force required to disrupt a surgical anastomosis.

Developmental divergence of sleep-wake patterns in orexin knockout and wild-type mice.

Narcolepsy, a disorder characterized by fragmented bouts of sleep and wakefulness during the day and night as well as cataplexy, has been linked in humans and nonhuman animals to the functional integrity of the orexinergic system. Adult orexin knockout mice and dogs with a mutation of the orexin receptor exhibit symptoms that mirror those seen in narcoleptic humans. As with narcolepsy, infant sleep-wake cycles in humans and rats are highly fragmented, with consolidated bouts of sleep and wakefulness developing gradually. Based on these common features of narcoleptics and infants, we hypothesized that the development of sleep-wake fragmentation in orexin knockout mice would be expressed as a developmental divergence between knockouts and wild-types, with the knockouts lagging behind the wild-types. We tested this hypothesis by recording the sleep-wake patterns of infant orexin knockout and wild-type mice across the first three postnatal weeks. Both knockouts and wild-types exhibited age-dependent, and therefore orexin-independent, quantitative and qualitative changes in sleep-wake patterning. At 3 weeks of age, however, by which time the sleep and wake bouts of the wild-types had consolidated further, the knockouts lagged behind the wild-types and exhibited significantly more bout fragmentation. These findings suggest the possibility that the fragmentation of behavioural states that characterizes narcolepsy in adults reflects reversion back toward the more fragmented sleep-wake patterns that characterize infancy.

Separable brainstem and forebrain contributions to ultrasonic vocalizations in infant rats.

Competing views persist concerning the functional significance of ultrasonic vocalizations (USVs) emitted by infant rats. One perspective holds that USVs result from an emotional state of fear and anxiety, the adult expression of which depends in part on forebrain mechanisms. Here the authors examine whether pups lacking forebrain input are capable of emitting USVs. Aspirations of neocortex and hippocampus or precollicular decerebrations were performed on 8-day-old rats. After the rats recovered, USV responses were recorded for 10 min at room temperature (Phase 1) followed by enhanced cooling for 20 min (Phase 2). Experimental pups emitted significantly fewer USVs than shams during Phase 1 but vocalized at similar rates during Phase 2. Thus, in infants, brainstem neural circuitry is sufficient to support emission of USVs.