A high-affinity cocaine binding site associated with the brain acid soluble protein 1.

Cocaine exerts its stimulant effect by inhibiting dopamine (DA) reuptake, leading to increased dopamine signaling. This action is thought to reflect the binding of cocaine to the dopamine transporter (DAT) to inhibit its function. However, cocaine is a relatively weak inhibitor of DAT, and many DAT inhibitors do not share cocaine's behavioral actions. Further, recent reports show more potent actions of the drug, implying the existence of a high-affinity receptor for cocaine. We now report high-affinity binding of cocaine associated with the brain acid soluble protein 1 (BASP1) with a dissociation constant (Kd) of 7 nM. Knocking down BASP1 in the striatum inhibits [3H]cocaine binding to striatal synaptosomes. Depleting BASP1 in the nucleus accumbens but not the dorsal striatum diminishes locomotor stimulation in mice. Our findings imply that BASP1 is a pharmacologically relevant receptor for cocaine.

Cocaine-induced locomotor stimulation involves autophagic degradation of the dopamine transporter.

Cocaine exerts its stimulant effect by inhibiting dopamine reuptake leading to increased dopamine signaling. This action is thought to reflect binding of cocaine to the dopamine transporter (DAT) to inhibit its function. However, cocaine is a relatively weak inhibitor of DAT, and many DAT inhibitors do not share the behavioral actions of cocaine. We previously showed that toxic levels of cocaine induce autophagic neuronal cell death. Here, we show that subnanomolar concentrations of cocaine elicit neural autophagy in vitro and in vivo. Autophagy inhibitors reduce the locomotor stimulant effect of cocaine in mice. Cocaine-induced autophagy degrades transporters for dopamine but not serotonin in the nucleus accumbens. Autophagy inhibition impairs cocaine conditioned place preference in mice. Our findings indicate that autophagic degradation of DAT modulates behavioral actions of cocaine.

High-Risk Palliative Care Patients' Knowledge and Attitudes about Hereditary Cancer Testing and DNA Banking.

Even at the end of life, testing cancer patients for inherited susceptibility may provide life-saving information to their relatives. Prior research suggests palliative care inpatients have suboptimal understanding of genetic importance, and testing may be underutilized in this clinical setting. These conclusions are based on limited research. This study aimed to estimate genetic testing prevalence among high-risk palliative care patients in a National Cancer Institute-designated comprehensive cancer center. We also aimed to understand these patients' understanding of, and attitudes toward, hereditary cancer testing and DNA banking. Palliative care in-patients with cancer completed structured interviews, and their medical records were reviewed. Among patients at high risk for hereditary cancer, we assessed history of genetic testing/DNA banking; and related knowledge and attitudes. Among 24 high-risk patients, 14 (58.3%) said they/their relatives had genetic testing or they had been referred for a genetics consultation. Of the remaining 10 patients, seven (70%) said they would "probably" or "definitely" get tested. Patients who had not had testing were least concerned about the impact of future testing on their family relationships; two (20%) said they were "extremely concerned" about privacy related to genetic testing. Of patients without prior testing, five (50%) said they had heard or read "a fair amount" about genetic testing. No high-risk patients had banked DNA. Overall, 23 (95.8%) said they had heard or read "almost nothing" or "relatively little" about DNA banking. Written materials and clinician discussion were most preferred ways to learn about genetic testing and DNA banking. Overall, this study demonstrates underutilization of genetics services at the end of life continues to be problematic, despite high patient interest.

Gastric intestinal metaplasia development in African American predominant United States population.

BACKGROUND: Gastric cancer significantly contributes to cancer mortality globally. Gastric intestinal metaplasia (GIM) is a stage in the Correa cascade and a premalignant lesion of gastric cancer. The natural history of GIM formation and progression over time is not fully understood. Currently, there are no clear guidelines on GIM surveillance or management in the United States. AIM: To investigate factors associated with GIM development over time in African American-predominant study population. METHODS: This is a retrospective longitudinal study in a single tertiary hospital in Washington DC. We retrieved upper esophagogastroduodenoscopies (EGDs) with gastric biopsies from the pathology department database from January 2015 to December 2020. Patients included in the study had undergone two or more EGDs with gastric biopsy. Patients with no GIM at baseline were followed up until they developed GIM or until the last available EGD. Exclusion criteria consisted of patients age < 18, pregnancy, previous diagnosis of gastric cancer, and missing data including pathology results or endoscopy reports. The study population was divided into two groups based on GIM status. Univariate and multivariate Cox regression was used to estimate the hazard induced by patient demographics, EGD findings, and Helicobacter pylori (H. pylori) status on the GIM status. RESULTS: Of 2375 patients who had at least 1 EGD with gastric biopsy, 579 patients were included in the study. 138 patients developed GIM during the study follow-up period of 1087 d on average, compared to 857 d in patients without GIM (P = 0.247). The average age of GIM group was 64 years compared to 56 years in the non-GIM group (P < 0.001). In the GIM group, adding one year to the age increases the risk for GIM formation by 4% (P < 0.001). Over time, African Americans, Hispanic, and other ethnicities/races had an increased risk of GIM compared to Caucasians with a hazard ratio (HR) of 2.12 (1.16, 3.87), 2.79 (1.09, 7.13), and 3.19 (1.5, 6.76) respectively. No gender difference was observed between the study populations. Gastritis was associated with an increased risk for GIM development with an HR of 1.62 (1.07, 2.44). On the other hand, H. pylori infection did not increase the risk for GIM. CONCLUSION: An increase in age and non-Caucasian race/ethnicity are associated with an increased risk of GIM formation. The effect of H. pylori on GIM is limited in low prevalence areas.

Palliative Care for Patients on Extracorporeal Membrane Oxygenation for COVID-19 Infection.

BACKGROUND: Critically ill patients with COVID-19 infection on extracorporeal membrane oxygenation (ECMO) face high morbidity and mortality. Palliative care consultation may benefit these patients and their families. Prior to the pandemic, our institution implemented a policy of automatic palliative care consultation for all patients on ECMO due to the high mortality, medical complexity, and psychosocial distress associated with these cases. OBJECTIVES: The main objective was to describe the role of the palliative care team for patients on ECMO for COVID-19 infection. The secondary objective was to describe the clinical outcomes for this cohort. DESIGN: Case series. SETTINGS/SUBJECTS: All patients age 18 or older infected by the novel coronavirus who required cannulation on ECMO from March through July of 2020, at an urban, academic medical center in the United States. Inter-disciplinary palliative care consultation occurred for all patients. RESULTS: Twenty-three patients (median age 43 years [range 28-64], mean body mass index 34.9 kg/m2 [SD 9.2], 65% Hispanic ethnicity) were cannulated on ECMO. Eleven patients died during the hospitalization (48%). Patients older than 50 years of age demonstrated a trend toward increased odds of death compared to those younger than 50 years of age (OR 9.1, P = 0.07). Patients received an average of 6.8 (SD 3.7) palliative clinical encounters across all disciplines. The actions provided by the palliative care team included psychosocial support and counseling, determination of surrogate decision maker (for 100% of patients), pain management (83%), and non-pain symptom management (83%). CONCLUSIONS: Here, we present one of the first studies describing the patient characteristics, outcomes, and palliative care actions for critically ill patients with COVID-19 on ECMO. Almost half of the patients in this cohort died during their hospitalization. Given the high morbidity and mortality of this condition, we recommend involvement of palliative care for patients/families with COVID-19 infection who are on ECMO. The impact of palliative care on patient and family outcomes, such as symptom control, satisfaction with communication, rates of anxiety, and grief experience merits further investigation.

The Role of Palliative Medicine in Assessing Hereditary Cancer Risk.

BACKGROUND:: Hereditary cancer assessment and communication about family history risks can be critical for surviving relatives. Palliative care (PC) is often the last set of providers before death. METHODS:: We replicated a prior study of the prevalence of hereditary cancer risk among patients with cancer receiving PC consultations, assessed the history in the electronic medical record (EMR), and explored patients' attitudes toward discussions about family history. This study was conducted at an academic urban hospital between June 2016 and March 2017. RESULTS:: The average age of the 75 adult patients with cancer was 60 years, 49 (55%) male and 49 (65%) white. A total of 19 (25%) patients had no clear documentation of family history in the EMR, sometimes because no family history was included in the admission template or an automatically imported template lacked content. In all, 24 (32%) patients had high-risk pedigrees that merited referral to genetic services. And, 48 (64%) patients thought that PC was an appropriate venue to discuss the implications of family history. The mean comfort level in addressing these questions was high. CONCLUSIONS:: At an academic center, 25% of patients had no family history documented in the EMR. And, 32% of pedigrees warranted referral to genetic services, which was rarely documented. There is substantial room for quality improvement for oncologists and PC specialists-often the last set of providers-to address family cancer risk before death and to increase use and ease of documenting family history in the EMR. Addressing cancer family history could enhance prevention, especially among high-risk families.