Pain hypersensitivity, sensorimotor impairment, and decreased muscle force in a novel rat model of radiation-induced peripheral neuropathy.

INTRODUCTION: Radiation-induced peripheral neuropathy is a rare, but serious complication often resulting in profound morbidity, life-long disability, and chronic debilitating pain. Unfortunately, this type of peripheral neuropathy is usually progressive, and almost always irreversible. To date, a standardized rat model of radiation-induced peripheral neuropathy has not been established. The purpose of the present study was to examine neuropathic pain, sensorimotor impairment, and muscle force parameters following the administration of a clinically relevant radiation dose in a rat model. METHODS: Ten rats were randomly assigned to one of two experimental groups: (1) radiation and (2) sham-radiated controls. Radiated animals were given a clinically relevant dose of 35 Gray (Gy) divided into five daily doses of 7 Gy/day. This regimen represents a human equivalent dose of 70 Gy, approximating the same dosage utilized for radiotherapy in oncologic patients. Sham-radiated controls were anesthetized and placed in the radiation apparatus but were not given radiation. All animals were tested for baseline values in both sensorimotor and pain behavioral tests. Sensorimotor testing consisted of the evaluation of walking tracks with the calculation of the Sciatic Functional Index (SFI). Pain-related behavioral measures consisted of mechanical allodynia (von Frey test), cold allodynia (Acetone test), and thermal allodynia (Hargreaves test). Animals were tested serially over an 8-week period. At the study endpoint, electrophysiological and muscle force assessments were completed, and histomorphometric analysis was performed on all sciatic nerves. RESULTS: Animals that underwent radiation treatment displayed significantly greater pain hypersensitivity to mechanical stimulation as compared to sham radiated controls from weeks 4 to 8 of testing. SFI values indicated sensorimotor impairments in the overground gait of radiated animals as compared to non-radiated animals. Furthermore, radiated animals displayed reduced twitch and tetanic muscle force when compared to sham radiated controls. CONCLUSIONS: A clinically relevant human equivalent dose of fractionated 35 Gy in rats established significant pain hypersensitivity, impairments in sensorimotor locomotion, and decreased muscle force capacity. This novel rodent model of radiation-induced peripheral neuropathy can be utilized to assess the potential efficacy of therapeutic treatments to either prevent or remediate this clinically debilitating condition.

The Impact of Ethnicity on Craniosynostosis in the United States.

While many studies have examined potential risk factors for nonsyndromic craniosynostosis, there have been no publications to date investigating the role of ethnicity in the United States. The current study was undertaken as the first multi-center investigation to examine the relationship between ethnicity and nonsyndromic craniosynostosis, looking at both overall prevalence as well as potential correlation between ethnicity and pattern of affected suture site. A chart review of patients diagnosed with nonsyndromic craniosynostosis treated at four major children's hospitals was performed to obtain ethnicity data. Analysis was preformed based on ethnic group as well as suture site affected. To account for potentialOne regional selection bias, the KID database (1997-2012) was utilized to identify all cases of craniosynostosis on a national level. This data was analyzed against birth rates by ethnicity obtained from CDC WONDER natality database.Amongst the 2112 cases of nonsyndromic craniosynostosis at all institutions, Caucasians and African Americans were consistently the predominant ethnic groups. There was a statistically significant difference in the distribution of affected suture type with African Americans more likely to present with unicoronal synostosis and Caucasians more likely to present with metopic synostosis (P = 0.005). The national data revealed that there were more cases of craniosynostosis in Caucasians and fewer in African Americans than expected when compared to population birth rates. Our findings demonstrate that the Caucasian race is associated with increased rates of synostosis.

Subclinical Peroneal Neuropathy: A Common, Unrecognized, and Preventable Finding Associated With a Recent History of Falling in Hospitalized Patients.

PURPOSE: Identification of modifiable risk factors for falling is paramount in reducing the incidence and morbidity of falling. Peroneal neuropathy with an overt foot drop is a known risk factor for falling, but research into subclinical peroneal neuropathy (SCPN) resulting from compression at the fibular head is lacking. The purpose of our study was to determine the prevalence of SCPN in hospitalized patients and establish whether it is associated with a recent history of falling. METHODS: We conducted a cross-sectional study of 100 medical inpatients at a large academic tertiary care hospital in St Louis, Missouri. General medical inpatients deemed at moderate to high risk for falling were enrolled in the summer of 2013. Patients were examined for findings that suggest peroneal neuropathy, fall risk, and a history of falling. Multivariate logistic regression was used to correlate SCPN with fall risk and a history of falls in the past year. RESULTS: The mean patient age was 53 years (SD = 13 years), and 59 patients (59%) were female. Thirty-one patients had examination findings consistent with SCPN. After accounting for various confounding variables within a multivariate logistic regression model, patients with SCPN were 4.7 times (95% CI, 1.4-15.9) more likely to report having fallen 1 or more times in the past year. CONCLUSIONS: Subclinical peroneal neuropathy is common in medical inpatients and is associated with a recent history of falling. Preventing or identifying SCPN in hospitalized patients provides an opportunity to modify activity and therapy, potentially reducing risk.

Metabolic reprogramming of macrophages: glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype.

Glucose is a critical component in the proinflammatory response of macrophages (MΦs). However, the contribution of glucose transporters (GLUTs) and the mechanisms regulating subsequent glucose metabolism in the inflammatory response are not well understood. Because MΦs contribute to obesity-induced inflammation, it is important to understand how substrate metabolism may alter inflammatory function. We report that GLUT1 (SLC2A1) is the primary rate-limiting glucose transporter on proinflammatory-polarized MΦs. Furthermore, in high fat diet-fed rodents, MΦs in crown-like structures and inflammatory loci in adipose and liver, respectively, stain positively for GLUT1. We hypothesized that metabolic reprogramming via increased glucose availability could modulate the MΦ inflammatory response. To increase glucose uptake, we stably overexpressed the GLUT1 transporter in RAW264.7 MΦs (GLUT1-OE MΦs). Cellular bioenergetics analysis, metabolomics, and radiotracer studies demonstrated that GLUT1 overexpression resulted in elevated glucose uptake and metabolism, increased pentose phosphate pathway intermediates, with a complimentary reduction in cellular oxygen consumption rates. Gene expression and proteome profiling analysis revealed that GLUT1-OE MΦs demonstrated a hyperinflammatory state characterized by elevated secretion of inflammatory mediators and that this effect could be blunted by pharmacologic inhibition of glycolysis. Finally, reactive oxygen species production and evidence of oxidative stress were significantly enhanced in GLUT1-OE MΦs; antioxidant treatment blunted the expression of inflammatory mediators such as PAI-1 (plasminogen activator inhibitor 1), suggesting that glucose-mediated oxidative stress was driving the proinflammatory response. Our results indicate that increased utilization of glucose induced a ROS-driven proinflammatory phenotype in MΦs, which may play an integral role in the promotion of obesity-associated insulin resistance.

Institutional Trends in Opioid Prescribing and Utilization after Primary Cleft Lip and Palate Repair.

BACKGROUND: Outpatient prescriptions for postoperative pain play an important role in the opioid epidemic. Prescribing guidelines are an effective target for intervention but require procedure-specific data to be successful. The aim of this study was to examine opioid prescribing patterns and pain control after primary cleft lip and palate repair at a large academic center. METHODS: Children undergoing cleft lip and palate repair from April of 2018 to July of 2019 were included in a prospective cohort study. Data on discharge prescriptions, refills, and emergency room visits were obtained from the medical record. Caregivers were surveyed 7 to 21 days after surgery regarding pain control, opioid use, education exposure, storage, and disposal. Chi-square tests and one-way analysis of variance were used to examine predictors of pain control, opioid consumption, safe storage, and disposal. RESULTS: After screening, 59 children were included in the study. Patients were 55.8 percent male with a median age of 12 months (interquartile range, 5 to 15). Ninety percent of patients received an opioid prescription at discharge with a mean quantity of 10 doses (interquartile range, 5 to 15). Ninety-seven percent of caregivers used adjunct medication. Opioids were given for a median of 3 days (interquartile range, 2 to 6.5). Seventy-six percent of caregivers gave less opioid than prescribed. There was no association between pain control and opioid quantity ( p = 0.68). Twenty-four percent of caregivers used locked storage. Thirty-four percent of respondents with leftover medication reported disposal. CONCLUSIONS: Opioids are often overprescribed after cleft lip and palate repair. Providers should consider limiting prescriptions to a 3-day supply to help reduce the quantity of opioids available in the community.

Management of Calcified Cephalohematoma of Infancy: The University of Michigan 25-Year Experience.

BACKGROUND: Cephalohematoma of infancy is the result of a subperiosteal blood collection that usually forms during birth-related trauma. A small proportion of cephalohematomas can calcify over time, causing a permanent calvarial deformity that is only correctable with surgery. The authors present a technique for the excision and reconstruction of calcified cephalohematoma and their management experience over the past 25 years. METHODS: All patients with a diagnosis of calcified cephalohematoma between 1994 and 2019 were identified. Patients were included if the diagnosis was confirmed by a pediatric plastic surgeon or a neurosurgeon. All patients underwent surgical evaluation followed by surgical intervention or observation. Patient demographics and potential risk factors for both surgical and nonsurgical groups were compared using chi-square or Fisher's exact test. Additional data were collected for the surgical cohort. RESULTS: Of 160 infants diagnosed with cephalohematoma, 72 met inclusion criteria. Thirty patients underwent surgical treatment. There was no significant difference in demographics, baseline characteristics, or potential risk factors between the operative and nonoperative groups. Mean age at the time of surgery was 8.6 months. Twenty-one surgical patients (70 percent) required inlay bone grafting. All surgery patients had improvement in calvarial shape. The main risk of surgery was blood loss requiring transfusion [eight patients (26.7 percent)]. Thirteen percent of patients experienced minor complications. CONCLUSIONS: This series of 72 children with calcified cephalohematomas, 30 of whom required surgical intervention, is one of the largest to date. The technique presented herein demonstrated excellent surgical outcomes by restoring normal cranial contours and was associated with a low complication profile. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Postoperative Ketorolac in Breast and Body Contouring Procedures: A Nationwide Claims Analysis.

BACKGROUND: Nonsteroidal antiinflammatory drugs are useful alternatives to narcotics for analgesia. However, concerns remain regarding their safety. The authors evaluated ketorolac use and complications. We hypothesized that no association between ketorolac and morbidity exists in patients undergoing body contouring. METHODS: Truven MarketScan claims database was analyzed for patients undergoing breast and body contouring surgery. Patients selected received ketorolac and were enrolled a minimum of 90 days. The authors performed a multivariable logistic regression to calculate risk of morbidity, adjusting for clinical and sociodemographic factors. RESULTS: Among the 106,279 patients enrolled, 4924 (4.6 percent) received postoperative ketorolac. In multivariable regression analysis, ketorolac was not associated with hematoma (OR, 1.20; 95 percent CI, 0.99 to 1.46; p > 0.05). There was an increased rate of reoperation within 72 hours (OR, 1.22; 95 percent CI, 1.00 to 1.49; p < 0.05; number needed to harm, 262 patients). Ketorolac was associated with fewer readmissions (OR, 0.76; 95 percent CI, 0.62 to 0.93; p < 0.05; number needed to treat, 87 patients), with a reduction in the rate of pain as a readmission diagnosis (0.6 percent versus 4.3 percent; p = 0.021). Ketorolac was associated with seroma, but this association may not be causal (OR, 1.28; 95 percent CI, 1.05 to 1.57; p < 0.05; number needed to harm, 247 patients). Ketorolac provided an estimated savings of $157 per patient. CONCLUSIONS: The benefits of ketorolac likely outweigh the risks after surgery. Absolute differences in reoperation rates were low, and improved rates of hospital admission impact cost savings. The authors advocate postoperative ketorolac once the wound is hemostatic. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.