The Use of Biomarkers in the Early Diagnosis of Septic Arthritis and Osteomyelitis-A Pilot Study.

BACKGROUND: The diagnosis of septic arthritis (SA) and osteomyelitis (OM) has remained challenging in the pediatric population, often accompanied by delays and requiring invasive interventions. The purpose of this pilot study is to identify a novel panel of biomarkers and cytokines that can accurately differentiate SA and OM at initial presentation using serum alone. METHODS: Twenty patients below 18 years old whose working diagnosis included SA (n=10) and OM (n=10) were identified. Serum was collected at initial evaluation. Each sample underwent seven ELISA [C1-C2, COMP, CS-846, hyaluronan, procalcitonin, PIIANP, C-terminal telopeptide of type II collagen (CTX-II)] and 65-plex cytokine panels. Principal component and Lasso regression analysis were performed to identify a limited set of predictive biomarkers. RESULTS: Mean age was 4.7 and 9.5 years in SA and OM patients, respectively (P=0.029). 50% of SA patients presented within 24 hours of symptom onset, compared with 0% of OM patients (P=0.033). 30% of SA patients were discharged home with an incorrect diagnosis and re-presented to the emergency department days later. At time of presentation: temperature ≥38.5°C was present in 10% of SA and 40% of OM patients (P=0.12), mean erythrocyte sedimentation rate (mm/h) was 51.6 in SA and 44.9 in OM patients (P=0.63), mean C-reactive protein (mg/dL) was 55.8 in SA and 71.8 in OM patients (P=0.53), and mean white blood cells (K/mm3) was 12.5 in SA and 10.4 in OM patients (P=0.34). 90% of SA patients presented with ≤2 of the Kocher criteria. 100% of SA and 40% of OM patients underwent surgery. 70% of SA cultures were culture negative, 10% MSSA, 10% Kingella, and 10% Strep pyogenes. 40% of OM cultures were culture negative, 50% MSSA, and 10% MRSA. Four biomarkers [CTx-II, transforming growth factor alpha (TGF-α), monocyte chemoattractant protein 1 (MCP-1), B cell-attracting chemokine 1] were identified that were able to classify and differentiate 18 of the 20 SA and OM cases correctly, with 90% sensitivity and 80% specificity. CONCLUSIONS: This pilot study identifies a panel of biomarkers that can differentiate between SA and OM at initial presentation using serum alone. LEVEL OF EVIDENCE: Level II-diagnostic study.

Analysis of 280 Magnetically Controlled Growing Rod Lengthenings Comparing External Remote Control Readouts and Radiographic Measurements: Impact of Patient and Deformity Factors.

BACKGROUND: This study aimed to assess the accuracy of the external remote control (ERC) digital readout to the radiographic measurement of magnetically controlled growing rod (MCGR) actuators undergoing lengthenings/expansions and to analyze the impact of patient and spinal deformity factors on the accuracy of the ERC digital readout. METHODS: Single-surgeon database at 2 tertiary-care pediatric hospitals identified early-onset scoliosis patients with MCGR constructs. There were 14 males and 16 females with a minimum of 2 lengthenings included in the analysis. ERC readouts at each lengthening were recorded. RESULTS: Sixty-six MCGR actuators were assessed in 30 patients which underwent 280 lengthenings (mean of 5.7 lengthenings). At individual lengthening sessions the ERC and radiographic measurements were correlated (r = 0.69, P<0.001). The summed radiographic measurements averaged 15% less than the summed ERC readouts (SD = 19%). The difference between the sum of radiographic measurements and ERCs was positively correlated with subsequent lengthenings (r = 0.94, P = 0.015). The accuracy of the ERC did not improve with increased grouped sessions (r = -0.54, P = 0.388) with no difference between the group with 2 and the group with ≥5 lengthenings (P = 0.670). In patients with dual rods, the difference was correlated between rods (r = 0.66, P<0.001) and the distraction of each rod was not significantly different from the other (P = 0.124). Patient weight correlated with the difference between the radiographs and ERC readouts (r = 0.27, P = 0.032). In patients with multiple grouped lengthenings, increased weight was positively correlated with an increase in measurement difference (mean r = 0.972). CONCLUSIONS: Summed radiographic measurements during lengthening sessions averaged 15% less than the summed ERC readouts. The accuracy of radiographic measurements did not increase when sessions were grouped together (2 vs. ≥5). There was no difference in the ERC accuracy over lengthening sessions early versus late. Patient weight, but not body mass index, was positively correlated with the discrepancy between the ERC and radiographic measures. LEVEL OF EVIDENCE: Level III.

Opioid Use Following Operatively Treated Pediatric Elbow and Femur Fractures.

BACKGROUND: Opioids are a commonly utilized component of pain management following pediatric extremity fractures, yet an increasing number of adolescents and children are falling victim to their negative effects. The purpose of this study was to examine opioid use in the pediatric fracture population by determining and comparing the average hospital opioid dosage utilized in the operative pediatric elbow and femur fractures and determining and comparing the average dose prescribed following operative treatment of elbow and femur fractures. METHODS: All elbow and femur fractures treated operatively between January and December 2016 were identified. Patients aged 0 to 17 years with closed injuries who presented to the emergency department (ED) within 24 hours of injury and underwent operative treatment were included. Demographic information, opioid and nonopioid analgesic medication doses administered in the ED and while inpatient, and postdischarge prescription information were recorded. Opioid doses were converted to oral morphine equivalents. RESULTS: In total, 91.9% and 78.1% of patients received opioids during the ED and inpatient periods, respectively. Only 30% of patients in either cohort received a nonopioid analgesic in the ED and only 44% received ibuprofen while inpatient. Average total opioid dose per hour of hospital stay was not significantly different between elbow fracture and femur fracture cohorts, which was unexpected. There was no significant difference between the average opioid dose or number of doses prescribed for postdischarge use between cohorts. CONCLUSIONS: This study provides data on average hospital opioid and nonopioid use following pediatric elbow and femur fractures. The results reveal inconsistent nonopioid analgesic use and similar hospital opioid use in elbow and femur fracture patients. This study provides baseline analgesic use data for future investigations. LEVEL OF EVIDENCE: Level IV.

Action control is mediated by prefrontal BDNF and glucocorticoid receptor binding.

Stressor exposure biases decision-making strategies from those based on the relationship between actions and their consequences to others restricted by stimulus-response associations. Chronic stressor exposure also desensitizes glucocorticoid receptors (GR) and diminishes motivation to acquire food reinforcement, although causal relationships are largely not established. We show that a history of chronic exposure to the GR ligand corticosterone or acute posttraining GR blockade with RU38486 makes rodents less able to perform actions based on their consequences. Thus, optimal GR binding is necessary for the consolidation of new response-outcome learning. In contrast, medial prefrontal (but not striatal) BDNF can account for stress-related amotivation, in that selective medial prefrontal cortical Bdnf knockdown decreases break-point ratios in a progressive-ratio task. Knockdown also increases vulnerability to RU38486. Despite the role of BDNF in dendritic spine reorganization, deep-layer spine remodeling does not obviously parallel progressive-ratio response patterns, but treatment with the Na(+)-channel inhibitor riluzole reverses corticosteroid-induced motivational deficits and restores prefrontal BDNF expression after corticosterone. We argue that when prefrontal neurotrophin systems are compromised, and GR-mediated hypothalamic-pituitary-adrenal axis feedback is desensitized (as in the case of chronic stress hormone exposure), amotivation and inflexible maladaptive response strategies that contribute to stress-related mood disorders result.

The role of chromogranin B in an animal model of multiple sclerosis.

Chromogranin B (CGB) is a high capacity, low affinity calcium binding protein in the endoplasmic reticulum (ER) that binds to the inositol 1,4,5 trisphosphate receptor (InsP3R) and amplifies calcium release from ER stores. Recently, it was discovered that levels of CGB-derived peptides are decreased in the cerebrospinal fluid of multiple sclerosis (MS) patients. One of the mechanisms by which neurodegeneration in MS is thought to occur is through increased levels of intra-axonal calcium. The combination of excess intracellular calcium and dysregulated levels of CGB in MS led us to hypothesize that CGB may be involved in MS pathophysiology. Here, we show in a mouse model of MS that CGB levels are elevated in neurons prior to onset of symptoms. Once symptoms develop, CGB protein levels increase with disease severity. Additionally, we show that elevated levels of CGB may have a role in the pathophysiology of MS and suggest that the initial elevation of CGB, prior to symptom onset, is due to inflammatory processes. Upon development of symptoms, CGB accumulation in neurons results from decreased ubiquitination and decreased secretion. Furthermore, we show that calpain activity is increased and levels of InsP3R are decreased. From these results, we suggest that the elevated levels of CGB and altered InsP3R levels may contribute to the axonal/neuronal damage and dysregulated calcium homeostasis observed in MS. Additionally, we propose that CGB can be a biomarker that predicts the onset and severity of disease in patients with MS.

Prevention of paclitaxel-induced peripheral neuropathy by lithium pretreatment.

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect that occurs in many patients undergoing chemotherapy. It is often irreversible and frequently leads to early termination of treatment. In this study, we have identified two compounds, lithium and ibudilast, that when administered as a single prophylactic injection prior to paclitaxel treatment, prevent the development of CIPN in mice at the sensory-motor and cellular level. The prevention of neuropathy was not observed in paclitaxel-treated mice that were only prophylactically treated with a vehicle injection. The coadministration of lithium with paclitaxel also allows for administration of higher doses of paclitaxel (survival increases by 60%), protects against paclitaxel-induced cardiac abnormalities, and, notably, does not interfere with the antitumor effects of paclitaxel. Moreover, we have determined a mechanism by which CIPN develops and have discovered that lithium and ibudilast inhibit development of peripheral neuropathy by disrupting the interaction between paclitaxel, neuronal calcium sensor 1 (NCS-1), and the inositol 1,4,5-trisphosphate receptor (InsP3R) to prevent treatment-induced decreases in intracellular calcium signaling. This study shows that lithium and ibudilast are candidate therapeutics for the prevention of paclitaxel-induced neuropathy and could enable patients to tolerate more aggressive treatment regimens.

C-terminal domain of chromogranin B regulates intracellular calcium signaling.

The versatility of intracellular calcium as a second messenger is seen in its ability to mediate opposing events such as neuronal cell growth and apoptosis. A leading hypothesis used to explain how calcium regulates such divergent signaling pathways is that molecules responsible for maintaining calcium homeostasis have multiple roles. For example, chromogranin B (CGB), a calcium binding protein found in secretory granules and in the lumen of the endoplasmic reticulum, buffers calcium and also binds to and amplifies the activity of the inositol 1,4,5-trisphosphate receptor (InsP(3)R). Previous studies have identified two conserved domains of CGB, an N-terminal domain (N-CGB) and a C-terminal domain (C-CGB). N-CGB binds to the third intraluminal loop of the InsP(3)R and inhibits binding of full-length CGB. This displacement of CGB decreases InsP(3)R-dependent calcium release and alters normal signaling patterns. In the present study, we further characterized the role of N-CGB and identified roles for C-CGB. The effect of N-CGB on calcium release depended upon endogenous levels of cellular CGB, whereas the regulatory effect of C-CGB was apparent regardless of endogenous levels of CGB. When either full-length CGB or C-CGB was expressed in cells, calcium transients were increased. Additionally, the calcium signal initiation site was altered upon C-CGB expression in neuronally differentiated PC12 and SHSY5Y cells. These results show that CGB has numerous regulatory roles and that CGB is a critical component in modulating InsP(3)R-dependent calcium signaling.

Treatment of paediatric Lisfranc injuries: A systematic review and introduction of a novel treatment algorithm.

Background: Pediatric Lisfranc injuries (PLI) are rare injuries that have few studies published about their occurrence and treatment in pediatric population. Due to this lack of information, the diagnostic criteria and surgical or non-surgical methods for treatment have not been clearly established within the pediatric orthopedic literature. The objective of this study was to review the published literature related to treatment options and develop a concise stepwise treatment algorithm for pediatric patients presenting with Lisfranc injuries. Methods: A systematic literature review was conducted using PubMed to find studies discussing the treatment of PLI with reported long-term outcomes. Data collection accounted for the mechanism of injury, diagnostic imaging modality used, injury type, fracture classification using the Myerson system, treatment method used, and postoperative complications. Results: An initial PubMed search revealed 290 articles, but only 10 studies fulfilled the criteria for in-depth review. A total of 114 patients were included in this review from the selected case reports and case series studies. Primary treatment methods were as follows: 44% (50/114) with open reduction internal fixation (ORIF) using Kirschner wires (K-wires) and/or screws, 3% (3/114) with closed reduction percutaneous fixation (CRPF), 4% (4/114) with suture-button constructs, 20% (23/114) with cast immobilization, and 29% (33/114) were described as not requiring reduction. Conclusion: There were two main limitations to this study. First, there are few published studies with longitudinal outcomes of PLI treatment. Second, some case series did not disclose which procedure a patient with post-treatment complications underwent. Therefore, an overall statistical analysis of success and failure rates with associated complications of each procedure could not be conducted. In conclusion, we found that a stepwise approach to evaluating conservative and surgical treatment options based on the presentation of the PLI should be utilized to optimize long-term outcomes.

Hip Surveillance in Children with Cerebral Palsy.

The hip is the second most common involved joint in cerebral palsy. Hip displacement occurs in more than 33% of children with cerebral palsy, with a higher prevalence in nonambulatory children. Hip displacement in this population is typically progressive. Hip dislocation can result in pain and difficulty with sitting and perineal care. Since early stage of hip displacement can be silent, and hip surveillance programs are recommended. Most programs use the degree of hip dysplasia and Growth Motor Function Classification System level for screening recommendations. Treatment depends on the degree of dysplasia, functional status of the patient, and patient's age.

Elevated expression of keratin 17 in oropharyngeal squamous cell carcinoma is associated with decreased survival.

BACKGROUND: Overexpression of keratin 17 (K17) is highly associated with poor prognosis in squamous cell carcinoma (SCC) of the cervix. This study was performed to (1) determine whether K17 may be a prognostic biomarker in head and neck squamous cell carcinoma (HNSCC) and (2) to establish if K17 expression is associated with human papillomavirus (HPV) status. METHODS: Immunohistochemical staining was performed for K17 of oral, oropharyngeal, and laryngeal SCCs, and normal oropharyngeal mucosa. The HPV status was determined using polymerase chain reaction (PCR). RESULTS: Elevated K17 expression was significantly associated with an overall decreased patient survival (P = .02) and, more specifically, in patients with oropharyngeal SCC (P = .01). When controlling for HPV status and tumor location K17 was still a significant predictor of survival (P = .01). CONCLUSION: Therefore, K17 is a novel prognostic biomarker of poor survival for patients with HNSCCs, controlling for anatomic site and HPV status.