Effects of remifentanil/histamine mixtures in rats responding under a choice procedure.

Intravenous drug self-administration remains the 'gold standard' for assessing abuse liability. Failure of a drug to maintain self-administration might indicate the absence of positive reinforcing effects but might also indicate the presence of aversive effects. Sensitivity to aversive and punishing effects of drugs (as well as nondrug stimuli) might collectively determine the likelihood of use, abuse and relapse. Using a choice procedure, this study compared the effects of remifentanil (mu opioid receptor agonist; 0.001-0.01 mg/kg/infusion) and histamine (H1-4 receptor agonist; 0.32-3.2 mg/kg/infusion), alone and in mixtures, to test the hypothesis that remifentanil/histamine mixtures are less reinforcing compared with remifentanil alone and less punishing compared with histamine alone. Male Sprague-Dawley rats (n = 10) chose between an intravenous infusion + a pellet and a pellet alone. Rats were indifferent to saline, chose remifentanil + a pellet over a pellet alone, and chose a pellet alone over histamine + a pellet. The effects of remifentanil/histamine mixtures generally were different from the constituent doses of histamine alone but not from remifentanil alone. A mixture containing 3.2 mg/kg/infusion histamine and either 0.001 or 0.0032 mg/kg/infusion remifentanil was not different from saline but was different from the effects of the constituent dose, insofar as choice increased compared with 3.2 mg/kg/infusion histamine alone and decreased compared with 0.001 or 0.0032 mg/kg/infusion remifentanil alone. Reinforcing doses of remifentanil combined with punishing doses of histamine can yield mixtures that are neither preferred nor avoided, offering 'proof-of-principle' for using drug mixtures to avoid adverse effects of opioid receptor agonists.

Impact of Fiberoptic Endoscopic Evaluation of Swallowing Outcomes and Dysphagia Management in Neurodegenerative Diseases.

OBJECTIVES/HYPOTHESIS: To determine the incidence of abnormal fiberoptic endoscopic evaluation of swallowing (FEES) findings in patients with progressive neurologic disorders and identify the most commonly implemented dysphagia management strategies. STUDY DESIGN: Retrospective Review. METHODS: A retrospective review was performed of patients with neurodegenerative disease who underwent FEES at a tertiary-care center between 2008 and 2019. Patient demographics, diagnosis, and Eating Assessment Tool-10 (EAT-10) scores were recorded. Rates of penetration, aspiration, and functional change in management (FCIM) to include dietary modifications, home exercises, swallow therapy, surgical intervention (injection augmentation or esophageal dilation), or alternative means of nutrition (i.e., percutaneous enteral gastrostomy [PEG] tube) were calculated. RESULTS: Two hundred nine FEES assessments were performed in 178 patients with a mean age of 64.8 years (standard deviation = ±14). The most common diagnoses were amyotrophic lateral sclerosis (32%) followed by Parkinson's disease or Parkinsonism (26%). FEES demonstrated penetration in 72.5% of patients and aspiration in 14.6%. Mean EAT-10 scores differed between patients with aspiration versus penetration versus normal FEES (24.7 vs. 14.9 vs. 13.9, respectively, P < .001). An FCIM was recommended in 88% of patients and most commonly included self-directed modifications (43%). Overall, 4.5% of patients underwent surgical intervention. A PEG tube was recommended for either supplemental or sole form of nutrition in 19% of the entire cohort. CONCLUSIONS: Most patients with neurodegenerative diseases presenting with dysphagia demonstrated abnormal FEES findings necessitating an FCIM, suggesting early dysphagia evaluation may be warranted in this cohort. These findings correlate with worsened EAT-10 scores in patients with aspiration or penetration on FEES. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:726-730, 2021.

Safety and efficacy of a novel cephalomedullary nail femoral shaft fractures: a retrospective observational cohort in 33 patients.

BACKGROUND: Despite advances in femoral shaft fracture fixation, the nonunion rate remains relatively high; and there is limited data on the efficacy and failure rate of specific implants. A novel cephalomedullary nail provides the ability to treat femur shaft fractures in isolation, with associated ipsilateral femur injuries, and provides various options for proximal and distal fixation exists on the market; but literature remains limited on the safety and efficacy of this implant. The aim of this study is to evaluate the early failure rate of this cephalomedullary nail, while comparing the nonunion rate to what is currently presented in the literature. This study is the first of its kind in evaluation of a specific implant for treatment of femoral shaft fractures and ipsilateral pathology. METHODS: Patients over 18 years of age, with traumatic femur shaft fractures, treated with this particular cephalomedullary nail and available for a minimum of 3-month follow-up were included for analysis. Data was collected by retrospective chart review and review of existing radiographs. Demographic data, injury details, AO/OTA fracture classification, and implant details were recorded for each patient. Primary outcome measured was implant failures (screw or nail breakage). Secondary outcomes measured included malunion, nonunion, deep infection, post-operative complications, and need for reoperation. RESULTS: Of the 33 patients included for analysis, 1 patient went on to non-union. There were no cases of implant failure. The single nonunion was a high-energy mechanism, open fracture, and higher level AO/OTA classification. The remaining 32 reached radiographic union at 3 months. CONCLUSION: The nonunion rate of this novel cephalomedullary nail is comparable to what is reported in the literature. This nail is a safe and effective implant to treat femoral shaft fractures with a variety of ipsilateral femoral shaft injuries and reliably leads fracture union. Further studies are needed analyzing implant failure and comparing specific implants.

Nuclear NADPH oxidase-4 associated with disease progression in renal cell carcinoma.

Nuclear NADPH oxidase-4 (Nox4) is a key component of metabolic reprogramming and is often overexpressed in renal cell carcinoma (RCC). However, its prognostic role in RCC remains unclear. Here we examined the significance of nuclear Nox4 on disease progression and development of drug resistance in advanced RCC. We analyzed human RCC tissue from multiple regions in the primary index tumor, cancer-associated normal adjacent parenchyma, intravascular tumor in locally advanced cancer patients. We found that the higher nuclear Nox4 expression was significantly associated with progression and death. These findings were consistent after controlling for other competing clinical variables. In contrast, patients with lower nuclear Nox4, even in higher stage RCC had better prognosis. We identified a subset of patients with high nuclear Nox4 who had rapid disease progression or died within 6 months of surgery. In addition, higher nuclear Nox4 level correlated with resistance to targeted therapy and immunotherapy. Western blotting performed on fresh human RCC tissue as well as cell-lines revealed increased nuclear Nox4 expression. Our data support an important prognostic role of Nox4 mediated regulation of RCC independent of other competing variables. Nox4 localizes to the nucleus in high-grade, high-stage RCC. Higher nuclear Nox4 has prognostic significance for disease progression, poor survival, and development of drug resistance in RCC.

Giant papillary conjunctivitis: A review.

Giant papillary conjunctivitis (GPC), which is characterized by the development of "giant" papillae on the superior tarsal conjunctiva, is a common complication in contact lens wearers. This condition can be associated with excessive mucus production, itching, blurry vision, and diminished contact lens tolerance. Risk factors for GPC include non-disposable lenses, infrequent lens replacement, long wearing time, inadequate lens hygiene, and atopy. Although the exact pathophysiology of GPC remains incompletely understood, it likely develops from the combination of mechanical trauma to the superior tarsal conjunctiva and an immunologic response by the conjunctiva to deposits on the anterior surface of the contact lens. With proper management, GPC has an excellent prognosis. In mild cases, prompt contact lens cessation is sufficient for the resolution of signs and symptoms. For more severe cases, the use of topical anti-histaminic agents is indicated. Uncommonly, topical steroids, non-steroidal anti-inflammatory agents, immunomodulatory medications, or very rarely surgery may be needed. In this review article, we provide a comprehensive review of the available literature on GPC, with an emphasis on recent findings and treatment advances for this common condition.