Loss of Intercalated Cells (ITCs) in the Mouse Amygdala of Tshz1 Mutants Correlates with Fear, Depression, and Social Interaction Phenotypes.

The intercalated cells (ITCs) of the amygdala have been shown to be critical regulatory components of amygdalar circuits, which control appropriate fear responses. Despite this, the molecular processes guiding ITC development remain poorly understood. Here we establish the zinc finger transcription factor Tshz1 as a marker of ITCs during their migration from the dorsal lateral ganglionic eminence through maturity. Using germline and conditional knock-out (cKO) mouse models, we show that Tshz1 is required for the proper migration and differentiation of ITCs. In the absence of Tshz1, migrating ITC precursors fail to settle in their stereotypical locations encapsulating the lateral amygdala and BLA. Furthermore, they display reductions in the ITC marker Foxp2 and ectopic persistence of the dorsal lateral ganglionic eminence marker Sp8. Tshz1 mutant ITCs show increased cell death at postnatal time points, leading to a dramatic reduction by 3 weeks of age. In line with this, Foxp2-null mutants also show a loss of ITCs at postnatal time points, suggesting that Foxp2 may function downstream of Tshz1 in the maintenance of ITCs. Behavioral analysis of male Tshz1 cKOs revealed defects in fear extinction as well as an increase in floating during the forced swim test, indicative of a depression-like phenotype. Moreover, Tshz1 cKOs display significantly impaired social interaction (i.e., increased passivity) regardless of partner genetics. Together, these results suggest that Tshz1 plays a critical role in the development of ITCs and that fear, depression-like and social behavioral deficits arise in their absence.SIGNIFICANCE STATEMENT We show here that the zinc finger transcription factor Tshz1 is expressed during development of the intercalated cells (ITCs) within the mouse amygdala. These neurons have previously been shown to play a crucial role in fear extinction. Tshz1 mouse mutants exhibit severely reduced numbers of ITCs as a result of abnormal migration, differentiation, and survival of these neurons. Furthermore, the loss of ITCs in mouse Tshz1 mutants correlates well with defects in fear extinction as well as the appearance of depression-like and abnormal social interaction behaviors reminiscent of depressive disorders observed in human patients with distal 18q deletions, including the Tshz1 locus.

The protein tyrosine phosphatase Shp2 is required for the generation of oligodendrocyte progenitor cells and myelination in the mouse telencephalon.

The protein tyrosine phosphatase Shp2 (PTPN11) is crucial for normal brain development and has been implicated in dorsal telencephalic neuronal and astroglia cell fate decisions. However, its roles in the ventral telencephalon and during oligodendrogenesis in the telencephalon remain largely unknown. Shp2 gain-of-function (GOF) mutations are observed in Noonan syndrome, a type of RASopathy associated with multiple phenotypes, including cardiovascular, craniofacial, and neurocognitive abnormalities. To gain insight into requirements for Shp2 (LOF) and the impact of abnormal Shp2 GOF mutations, we used a Shp2 conditional mutant allele (LOF) and a cre inducible Shp2-Q79R GOF transgenic mouse in combination with Olig2(cre/+) mice to target embryonic ventral telencephalic progenitors and the oligodendrocyte lineage. In the absence of Shp2 (LOF), neuronal cell types originating from progenitors in the ventral telencephalon were generated, but oligodendrocyte progenitor cell (OPC) generation was severely impaired. Late embryonic and postnatal Shp2 cKOs showed defects in the generation of OPCs throughout the telencephalon and subsequent reductions in white matter myelination. Conversely, transgenic expression of the Shp2 GOF Noonan syndrome mutation resulted in elevated OPC numbers in the embryo and postnatal brain. Interestingly, expression of this mutation negatively influenced myelination as mice displayed abnormal myelination and fewer myelinated axons in the white matter despite elevated OPC numbers. Increased proliferating OPCs and elevated MAPK activity were also observed during oligodendrogenesis after expression of Shp2 GOF mutation. These results support the notion that appropriate Shp2 activity levels control the number as well as the differentiation of oligodendrocytes during development.

Psychological Distress in Young Adults with Acute Myeloid Leukemia Undergoing Induction Chemotherapy.

Young adults (YAs), aged 18-39 years, with acute myeloid leukemia (AML) navigate life disruptions amid an unpredictable illness trajectory. We conducted a secondary analysis of patient-reported outcomes for hospitalized YAs with high-risk AML receiving intensive chemotherapy, collected during a multisite randomized clinical trial. Of the 160 patients, 14 (8.8%) were YAs. At week 2 of hospitalization, YAs demonstrated significant worse quality of life (ß = -18.27; p = 0.036), higher anxiety (ß = 2.72; p = 0.048), and higher post-traumatic stress disorder (PTSD; ß = 10.34; p = 0.007) compared with older adults. Our analysis demonstrated a longitudinal presence of anxiety and PTSD, suggesting persistent unmet psychological needs for YAs with AML.

Impact of Referring Team Characteristics on Inpatient Palliative Care Consultation Rate at a Comprehensive Cancer Center.

Background: No prior study addresses the impact of admitting team characteristics on inpatient palliative care (PC) consultation rate in cancer patients. Understanding consultation rate differences among admitting service types may reveal PC access disparities for patients who would benefit from consultation. Aim: To determine the impact of admitting service characteristics (teaching vs. nonteaching and surgical vs. medical) on inpatient PC consultation rates. Methods: A six-month cross-sectional study was performed at an academic comprehensive cancer center. Inpatient PC consultations and follow-up visits were compared to total admissions by admitting service category. Results: Five thousand six hundred ninety-seven admissions resulted in 710 new PC consultations and 2494 follow-up visits. Patients admitted to medical services had highest odds of PC consultation, while data for teaching services were mixed. There was no difference in follow-up visits. Conclusions: Significant differences between medical and surgical service PC consultation rates may indicate specialty PC access disparities solely based on their admitting service.

Prospective Study of a Novel Risk Stratification Process for Opioid-Related Harm Reduction in Cancer Patients Seen in an Outpatient Palliative Care Clinic.

Background: Oncologists and palliative specialists prescribe opioids for millions of cancer patients despite limited research on effective screening and mitigation strategies to reduce risk of opioid-related harm in that population. Objective: To evaluate the efficacy of a novel opioid risk stratification process for predicting significant aberrant behaviors (SABs) related to prescribed opioid medications. Design and Setting/Subjects: This is a prospective, longitudinal study of 319 consecutive patients referred to an outpatient palliative care clinic between 2010 and 2012, a period during which prescription opioid-related deaths began to increase in the United States. Measures: Patients completed a psychodiagnostic/substance use risk assessment with a licensed clinical psychologist or social worker at the initial palliative clinic visit. Patients were assigned to Low-, Moderate-, or High-Risk groups based on predetermined stratification criteria and were managed via an opioid harm reduction approach. The primary dependent measure was the presence of at least one SAB after the initial visit. Results: Eighteen percent of patients (n = 56) demonstrated at least one major aberrant behavior. Odds of future aberrant behavior was 15 times greater in the High-Risk versus the Low-Risk category. Five risk factors significantly enhanced our risk model: age 18 to 45 years, job instability, history of bipolar diagnosis, history of substance abuse, and theft. Conclusion: Our risk stratification process provides a useful model for predicting those at greatest risk of future aberrant behaviors and most in need of comanagement. We recommend additional studies to test our proposed streamlined risk stratification tool.

Novel Use of Atomized Intravenous Ketamine Solution for the Topical Treatment of Intranasal Mucositis Pain: A Case Report.

Context: Treatment-induced mucositis commonly affects cancer patients, and ketamine oral rinse solution has shown efficacy for refractory pain. Although intranasal ketamine as systemic therapy has previously been studied, there are no reports on intranasal ketamine spray for topical pain treatment. Objective: To present the novel use of atomized intravenous ketamine solution for topical treatment of sinonasal mucositis pain. Patient case: A patient with sinonasal undifferentiated carcinoma presented with refractory treatment-related intranasal mucositis pain. Following initiation of atomized ketamine solution delivered topically into the nostrils, pain improved, and opioid use decreased. After dose adjustment for confusion, the patient continued ketamine therapy for several weeks with good effect. Conclusion: Atomized ketamine solution delivered intranasally may be a safe and effective topical treatment for mucositis pain of the sinuses. Interpretation of safety of the initial dosing used was affected by several confounding factors. However, a reduced dose appeared efficacious and was well tolerated.

Palliative Care Referral Patterns for Adolescent and Young Adult Patients at a Comprehensive Cancer Center.

Palliative care (PC) serves a valuable role throughout the disease trajectory for adolescents and young adults (AYAs) living with cancer. A 3-year retrospective chart review was performed to characterize AYA PC referral patterns in patients aged 18-39 years to identify strategies for improving PC access. Despite known benefits, AYA referrals to PC during oncologic treatment occurred only for a small percentage of eligible patients (8.4%), largely occurred in the inpatient setting (73%), and were more likely in specific cancer types with high symptom burden and/or poor survival, with the greatest penetrance noted in lung cancer (51%).

Top Ten Tips Palliative Care Clinicians Should Know About Medical Decision-Making Capacity Assessment.

Palliative care (PC) clinicians treat seriously ill patients who are at increased risk for compromised decision-making capacity (DMC). These patients face profound and complex questions about which treatments to accept and which to decline. PC clinicians, therefore, have the especially difficult task of performing thorough, fair, and accurate DMC assessments in the face of the complex effects of terminal illness, which may be complicated by fluctuating acute medical conditions, mental illness, or cognitive dysfunction. This study, written by a team of clinicians with expertise in PC, ethics, psychiatry, pediatrics, and geriatrics, aims to provide expert guidance to PC clinicians on best practice for complex DMC assessment.

Top Ten Tips Palliative Care Clinicians Should Know About Opioid Use Disorder.

Since the prevalence of substance use disorders, and opioid use disorder (OUD) specifically, remains high and represents a public health crisis, it is critical that palliative care (PC) providers have a broad understanding of this class of chronic, yet treatable, diseases. Conceptualizing stigma associated with OUD, treatment modalities available, and educational opportunities are key factors in providing patient-centered care. A solid foundation of knowledge about OUD in the setting of serious illness is also crucial as PC providers often recommend or prescribe opioids for symptom management in patients who also have OUD. Furthermore, the PC interdisciplinary team is particularly well poised to care for patients suffering from OUD due to the inherently holistic approach already present in the specialty of PC. This article offers PC teams a framework for understanding the diagnosis and treatment of OUD, methods for performing risk stratification and monitoring, and an overview of opportunities to enhance our care of PC patients with OUD.