A Paranigral VTA Nociceptin Circuit that Constrains Motivation for Reward.

Nociceptin and its receptor are widely distributed throughout the brain in regions associated with reward behavior, yet how and when they act is unknown. Here, we dissected the role of a nociceptin peptide circuit in reward seeking. We generated a prepronociceptin (Pnoc)-Cre mouse line that revealed a unique subpopulation of paranigral ventral tegmental area (pnVTA) neurons enriched in prepronociceptin. Fiber photometry recordings during progressive ratio operant behavior revealed pnVTAPnoc neurons become most active when mice stop seeking natural rewards. Selective pnVTAPnoc neuron ablation, inhibition, and conditional VTA nociceptin receptor (NOPR) deletion increased operant responding, revealing that the pnVTAPnoc nucleus and VTA NOPR signaling are necessary for regulating reward motivation. Additionally, optogenetic and chemogenetic activation of this pnVTAPnoc nucleus caused avoidance and decreased motivation for rewards. These findings provide insight into neuromodulatory circuits that regulate motivated behaviors through identification of a previously unknown neuropeptide-containing pnVTA nucleus that limits motivation for rewards.

Documentation of Sepsis in Patients Meeting Pediatric Sepsis Criteria: An Area for Improvement.

OBJECTIVE: Documentation is a critical aspect for properly evaluating a patient's medical status. In order to accurately diagnose sepsis promptly, the need for proper documentation becomes even more necessary. We conducted a retrospective chart review to assess accuracy and frequency of sepsis documentation by electronic medical records (EMR) review. The patients are children aged 0 to 18 years of age in whom the sepsis trigger tool fired in the EMR and were admitted on the inpatient floor or pediatric intensive care unit. METHODS: An EMR sepsis notification alert is currently utilized by our institution. Two pediatric intensivists reviewed the EMR charts of hospitalized, pediatric patients in whom the notification fired. The primary outcome was to identify the patients who met criteria for sepsis according to the 2005 International Pediatric Consensus Conference Guidelines. In patients who met the criteria, physician charting was inspected manually to evaluate documentation of sepsis and/or septic shock within 24 hours of meeting sepsis criteria. RESULTS: Using the 2005 International Pediatric Consensus Conference Guidelines, 359 patients met sepsis criteria. Of those, 24 (7 percent) were documented to have sepsis and/or septic shock in the EMR. Sixteen of those patients had septic shock, while the remaining eight had sepsis. CONCLUSION: Although sepsis is not uncommon, it is often not documented appropriately in electronic medical records. Hypothesized explanations include difficulty in diagnosing sepsis and using alternative diagnoses. This study demonstrates the ambiguity of the current pediatric sepsis criteria and difficulty capturing this diagnosis in the EMR.

Use of Motivational Interviewing Techniques by Student Volunteers to Reduce Substance Use in Coyote Clinic Patients.

INTRODUCTION: Nationally, free clinics report 18.5% of clients have a substance use disorder but few clinics have treatment resources on site. In 2014, 63,000 people in South Dakota needed but did not receive treatment for substance abuse. The Coyote Clinic (CC), a student-run free clinic, focuses on acute problems, making it difficult to manage and follow-up on long-term substance abuse disorders. Motivational interviewing (MI) is a style of counseling that has shown efficacy in producing change in behavior among patients who suffer from substance abuse in just one session. METHODS: A MI instructional session was given to all third-year medical students with a pre- and post-course survey to determine understanding and its application. For 21 weeks in the CC, a survey about substance use and willingness to change behavior was distributed to patients before and after the student interview. Student volunteers also responded to a post-clinic survey about their use of MI during the patient visit. RESULTS: Students showed a 17% increase in confidence in discussing substance use with patients and a 47% increase in confidence in applying MI techniques after the instructional session. At CC, 54.5% of patients reported substance use and 16.7% of those patients responded that they would consider quitting in the next month after the student interview. In the post-clinic survey, students rated an average of 4.21 out of 5 on comfort level in discussing excessive substance use. CONCLUSION: MI training expanded student volunteers' insight into treatment of substance use disorders and increased students' confidence when advising patients about substance abuse. Patients showed more willingness to change substance abuse behaviors after their student interviews. This project helps address substance use in student-run free clinics with limited resources and minimal follow up.

A phase 1 evaluation of the safety and tolerability of niraparib in combination with everolimus in advanced ovarian and breast cancers.

OBJECTIVES: Phase 1 trial to determine the safety and tolerability of everolimus and niraparib in patients with advanced ovarian and breast malignancies. RESULTS: Fourteen heavily pretreated patients were enrolled (12 high-grade serous ovarian cancer, 1 clear cell ovarian cancer, and 1 triple negative breast cancer). All patients were PARP naïve and received comprehensive genomic profiling prior to enrollment. Two DLTs were experienced in cohort 2 (niraparib 200 mg daily and everolimus 5 mg 3 days per week) with one patient experiencing prolonged thrombocytopenia and the other experiencing severe hypertension. Four additional patients were enrolled after dose de-escalation with one patient again experiencing severe hypertension leading to conclusion of the study. The most frequent grade 3 or greater adverse events were thrombocytopenia, hypertension, anemia, fatigue, neutropenia, and elevated alkaline phosphatase. Two patients had a PR and five patients had SD. ORR was 18% and the CBR was 45% in 11 evaluable patients. Median PFS was 6 months, and median OS is approximately 18 months with three patients still alive at the data cutoff. CONCLUSIONS: The combination of everolimus and niraparib demonstrated significant toxicity at lower doses and is not feasible due to rapid onset and severe hypertension. This limitation possibly blunted the efficacy of the combination as PFS was modest, but OS was surprisingly robust due to three patients with ovarian cancer remaining alive with platinum refractory disease. Further investigation of multiagent blockade of the PI3K pathway combined with PARP is warranted.

Metabolic parameters and long-term antipsychotic treatment: a comparison between patients treated with clozapine or olanzapine.

OBJECTIVES: This study was undertaken to examine if patients exhibit more pronounced metabolic abnormalities after 8-year treatment with clozapine or olanzapine than before, and also to investigate whether there exist any differences between long-term clozapine and olanzapine therapies regarding metabolic side- effects. METHODS: Fifty psychiatric outpatients diagnosed with schizophrenia or schizoaffective disorder and on treatment with clozapine or olanzapine were studied during 8 years. Fasting blood or serum samples for glucose, lipids, prolactin and antipsychotic drug concentrations were analyzed. In addition, body mass index was calculated. RESULTS: More patients treated with olanzapine compared with those treated with clozapine ended with their medication, in most cases because of diabetes mellitus and/or hyperlipidemia, during the 8-year follow-up. Also more patients treated with olanzapine compared with those treated with clozapine developed manifest diabetes mellitus during the 8-year period. Prolactin levels were higher in the patients treated with olanzapine compared with in those treated with clozapine at study start, but there were no differences in the other parameters between the treatment groups at study start. In the patients remaining on their medication all 8 years, the glucose level increased over time in the clozapine group, but not in the olanzapine group, whereas body mass index and lipids were unchanged over time in both treatment groups. CONCLUSIONS: Our findings point to that both olanzapine and clozapine long-term treatments cause development of hyperglycemia and/or hyperlipidemia. Furthermore, olanzapine long-term treatment seems to more often lead to development of manifest diabetes mellitus than long-term treatment with clozapine.

Attenuation of Ischemic Stroke-Caused Brain Injury by a Monoamine Oxidase Inhibitor Involves Improved Proteostasis and Reduced Neuroinflammation.

Mitochondrial dysfunction and oxidative stress play a key role in ischemia/reperfusion (I/R) induced brain injury. We previously showed that ubiquilin-1 (Ubqln1), a ubiquitin-like protein, improves proteostasis and protects brains against oxidative stress and I/R induced brain injury. We demonstrate here that nialamide (NM), a non-selective monoamine oxidase (MAO) inhibitor, upregulated Ublqn1 and protected neurons from oxygen-glucose deprivation- and I/R-caused cell death in in vitro and in vivo, respectively. Post-ischemic administration of the NM in a stroke mouse model even at 3 h following I/R still reduced neuronal injury and improved functional recovery and survival. Treating stroke animals with NM also increased the association of Ubqln1 with mitochondria and decreased the total oxidized and polyubiquitinated protein levels. Intriguingly, NM-enhanced proteostasis was also associated with reduced I/R-caused neuroinflammation, as reflected by attenuated activation of microglia and astrocytes as well as reduced TNF-α level. Thus, our results suggest that MAO inhibition-induced neuroprotection following I/R involves improved proteostasis and reduced neuroinflammation.

Therapeutic Role of a Cysteine Precursor, OTC, in Ischemic Stroke Is Mediated by Improved Proteostasis in Mice.

Oxidative stress aggravates brain injury following ischemia/reperfusion (I/R). We previously showed that ubiquilin-1 (Ubqln1), a ubiquitin-like protein, improves proteostasis and protects brains against oxidative stress and I/R-induced brain injury. Here, we demonstrate that a small molecule compound, L-2-oxothiazolidine-4-carboxylic acid (OTC) that functions as a precursor of cysteine, upregulated Ubqln1 and protected cells against oxygen-glucose deprivation-induced cell death in neuronal cultures. Further, the administration of OTC either at 1 h prior to ischemia or 3 h after the reperfusion significantly reduced brain infarct injury and improved behavioral outcomes in a stroke model. Administration of OTC also increased glutathione (GSH) level and decreased superoxide production, oxidized protein, and neuroinflammation levels in the penumbral cortex after I/R in the stroke mice. Furthermore, I/R reduced both Ubqln1 and the glutathione S-transferase protein levels, whereas OTC treatment restored both protein levels, which was associated with reduced ubiquitin-conjugated protein level. Interestingly, in the Ubqln1 knockout (KO) mice, OTC treatment showed reduced neuroprotection and increased ubiquitin-conjugated protein level when compared to the similarly treated non-KO mice following I/R, suggesting that OTC-medicated neuroprotection is, at least partially, Ubqln1-dependent. Thus, OTC is a potential therapeutic agent for stroke and possibly for other neurological disorders and its neuroprotection involves enhanced proteostasis.

Overexpression of Ubiquilin-1 Alleviates Alzheimer's Disease-Caused Cognitive and Motor Deficits and Reduces Amyloid-ß Accumulation in Mice.

Ubiquilin-1 (Ubqln1) is a ubiquitin-like protein that has been implicated in Alzheimer's disease (AD). However, whether Ubqln1 modulates learning and memory and alters AD-like behavior and/or pathology has not been determined in animal models. To understand the function of Ubqln1 in vivo, we previously generated Ubqln1 transgenic (TG) mice that overexpress mouse Ubqln1. With the model, we here characterized the TG mouse cognitive behaviors and found that Ubqln1 TG mice showed better spatial learning and memory capabilities than their wild-type littermates in both radial arm water maze and Y-maze tests. Additionally, we crossed the Ubqln1 TG mice with the AßPPswe/PSEN1dE9 double transgenic AD mouse to generate the AD/Ubqln1 triple TG (AD/TG) mice. Our results suggest that at 12 months of age following the onset of AD, AD/TG mice showed better spatial learning and memory than AD mice. AD/TG mice also exhibited better motor function than AD mice at the same age. Furthermore, compared to AD mice, AD/TG mice showed significant reduction in amyloid-ß 40 (Aß40) and Aß42 levels in the cerebral cortex and in the hippocampus at the post-onset stage. The number of Aß plaques was significantly decreased in the cerebral cortex of AD/TG mice at this post-onset stage. Moreover, mature AßPP level in AD/TG hippocampus was lower than that in AD hippocampus. These data not only provide a direct link between overexpression of Ubqln1 and altered learning and memory, but also raise the possibility that Ubqln1 is a potential therapeutic target for treating AD and possibly other neurodegenerative disorders.

Reduced body weight gain in ubiquilin-1 transgenic mice is associated with increased expression of energy-sensing proteins.

Ubiquilin-1 (Ubqln1), a ubiquitin-like protein, is implicated in a variety of pathophysiological processes, but its role in mediating body weight gain or metabolism has not been determined. Here, we demonstrate that global overexpression of Ubqln1 in a transgenic (Tg) mouse reduces the animal's body weight gain. The decreased body weight gain in Tg mice is associated with lower visceral fat content and higher metabolic rate. The Ubqln1 Tg mice exhibited reduced leptin and insulin levels as well as increased insulin sensitivity manifested by homeostatic model assessment of insulin resistance. Additionally, the reduced body weight in Tg mice was associated with the upregulation of two energy-sensing proteins, sirtuin1 (SIRT1) in the hypothalamus and AMP-activated protein kinase (AMPK) in the skeletal muscle. Consistent with the in vivo results, overexpression of Ubqln1 significantly increased SIRT1 and AMPK levels in the mouse embryonic fibroblast cell culture. Thus, our results not only establish the link between Ubqln1 and body weight regulation but also indicate that the metabolic function of Ubqln1 on body weight may be through regulating energy-sensing proteins.