Effects of Neonatal Hypoxic-Ischemic Injury on Brain Sterol Synthesis and Metabolism.

BACKGROUND: Neonatal hypoxic-ischemic brain injury (HIBI) results from disruptions to blood supply and oxygen in the perinatal brain. The goal of this study was to measure brain sterol metabolites and plasma oxysterols after injury in a neonatal HIBI mouse model to assess for potential therapeutic targets in the brain biochemistry as well as potential circulating diagnostic biomarkers. METHODS: Postnatal day 9 CD1-IGS mouse pups were randomized to HIBI induced by carotid artery ligation followed by 30 minutes at 8% oxygen or to sham surgery and normoxia. Brain tissue was collected for sterol analysis by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Plasma was collected for oxysterol analysis by LC-MS/MS. RESULTS: There were minimal changes in brain sterol concentrations in the first 72 hours after HIBI. In severely injured brains, there was a significant increase in desmosterol, 7-DHC, 8-DHC, and cholesterol 24 hours after injury in the ipsilateral tissue. Lanosterol, 24-dehydrolathosterol, and 14-dehydrozymostenol decreased in plasma 24 hours after injury. Severe neonatal HIBI was associated with increased cholesterol and sterol precursors in the cortex at 24 hours after injury. CONCLUSIONS: Differences in plasma oxysterols were seen at 24 hours but were not present at 30 minutes after injury, suggesting that these sterol intermediates would be of little value as early diagnostic biomarkers.

The Impact of Prematurity at Birth on Short-Term Postoperative Outcomes Following Posterior Spinal Fusion for Adolescent Idiopathic Scoliosis.

Prematurity is associated with surgical complications. This study sought to determine the risk of prematurity on 30-day complications, reoperations, and readmissions following ≥7-level PSF for AIS which has not been established. Utilizing the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP)-Pediatric dataset, all AIS patients undergoing ≥7-level PSF from 2012-2016 were identified. Cases were 1:1 propensity score-matched to controls by age, sex, and number of spinal levels fused. Prematurity sub-classifications were also evaluated: extremely (<28 weeks), very (28-31 weeks), and moderate-to-late (32-36 weeks) premature. Univariate analysis with post hoc Bonferroni compared demographics, hospital parameters, and 30-day outcomes. Multivariate logistic regression identified independent predictors of adverse 30-day outcomes. 5531 patients (term = 5099; moderate-to-late premature = 250; very premature = 101; extremely premature = 81) were included. Premature patients had higher baseline rates of multiple individual comorbidities, longer mean length of stay, and higher 30-day readmissions and infections than the term cohort. Thirty-day readmissions increased with increasing prematurity. Very premature birth predicted UTIs, superficial SSI/wound dehiscence, and any infection, and moderate-to-late premature birth predicted renal insufficiency, deep space infections, and any infection. Prematurity of AIS patients differentially impacted rates of 30-day adverse outcomes following ≥7-level PSF. These results can guide preoperative optimization and postoperative expectations.

Neonatal Hypoxic-Ischemic Brain Injury Alters Brain Acylcarnitine Levels in a Mouse Model.

Hypoxic-ischemic brain injury (HIBI) leads to depletion of ATP, mitochondrial dysfunction, and enhanced oxidant formation. Measurement of acylcarnitines may provide insight into mitochondrial dysfunction. Plasma acylcarnitine levels are altered in neonates after an HIBI, but individual acylcarnitine levels in the brain have not been evaluated. Additionally, it is unknown if plasma acylcarnitines reflect brain acylcarnitine changes. In this study, postnatal day 9 CD1 mouse pups were randomized to HIBI induced by carotid artery ligation, followed by 30 min at 8% oxygen, or to sham surgery and normoxia, with subgroups for tissue collection at 30 min, 24 h, or 72 h after injury (12 animals/group). Plasma, liver, muscle, and brain (dissected into the cortex, cerebellum, and striatum/thalamus) tissues were collected for acylcarnitine analysis by LC-MS. At 30 min after HIBI, acylcarnitine levels were significantly increased, but the differences resolved by 24 h. Palmitoylcarnitine was increased in the cortex, muscle, and plasma, and stearoylcarnitine in the cortex, striatum/thalamus, and cerebellum. Other acylcarnitines were elevated only in the muscle and plasma. In conclusion, although plasma acylcarnitine results in this study mimic those seen previously in humans, our data suggest that the plasma acylcarnitine profile was more reflective of muscle changes than brain changes. Acylcarnitine metabolism may be a target for therapeutic intervention after neonatal HIBI, though the lack of change after 30 min suggests a limited therapeutic window.

Cholesterol metabolism and brain injury in neonatal encephalopathy.

Neonatal encephalopathy (NE) results from impaired cerebral blood flow and oxygen delivery to the brain. The pathophysiology of NE is complex and our understanding of its underlying pathways continues to evolve. There is considerable evidence that cholesterol dysregulation is involved in several adult diseases, including traumatic brain injury, stroke, Huntington's disease, and Parkinson's disease. Although the research is less robust in pediatrics, there is emerging evidence that aberrations in cholesterol metabolism may also be involved in the pathophysiology of neonatal NE. This narrative review provides an overview of cholesterol metabolism in the brain along with several examples from the adult literature where pathologic alterations in cholesterol metabolism have been associated with inflammatory and ischemic brain injury. Using those data as a background, the review then discusses the current preclinical data supporting the involvement of cholesterol in the pathogenesis of NE as well as how brain-specific cholesterol metabolites may serve as serum biomarkers for brain injury. Lastly, we review the potential for using the cholesterol metabolic pathways as therapeutic targets. Further investigation of the shifts in cholesterol synthesis and metabolism after hypoxia-ischemia may prove vital in understanding NE pathophysiology as well as providing opportunities for rapid diagnosis and therapeutic interventions. IMPACT: This review summarizes emerging evidence that aberrations in cholesterol metabolism may be involved in the pathophysiology of NE. Using data from NE as well as analogous adult disease states, this article reviews the potential for using cholesterol pathways as targets for developing novel therapeutic interventions and using cholesterol metabolites as biomarkers for injury. When possible, gaps in the current literature were identified to aid in the development of future studies to further investigate the interactions between cholesterol pathways and NE.

Verification of Diagnosis in Tuberculosis: A Case Report and Discussion.

Tuberculosis (TB), caused by strains of Mycobacterium tuberculosis complex (M. tuberculosis), is a pulmonary infection that is spread by airborne droplet transmission. The development and spread of drug-resistant strains of M. tuberculosisgreatly jeopardize TB control efforts. We report the case of a previously healthy 43-year-old male, visiting from China, who presented to the emergency department complaining of hemoptysis of 10 days' duration. Cultures were positive for acid fast bacteria and negative for fungi. M. tuberculosis infection was confirmed by a deoxyribonucleic acid (DNA) probe. The patient was initially started on first-line therapy of isoniazid, rifampin, pyrazinamide, and ethambutol, with pyridoxine. His country of origin, China, increased suspicion for drug-resistant tuberculosis. Two weeks later, susceptibility testing of the M. tuberculosis isolate showed resistance to isoniazid, pyrazinamide, and ethambutol. Therapy was subsequently changed to amikacin, linezolid, moxifloxacin, and rifampin. The isolate was subsequently sent to the Center for Disease Control (CDC) for evaluation. Repeat testing showed that the isolate was susceptible to rifampin, pyrazinamide, and ethambutol. The patient was then restarted on his initial anti-TB regimen and was able to return to China. The main goals for the treatment of TB are to treat the individual patient and to minimize transmission. Clues that point to the possibility of multiple drug resistant tuberculosis (MDR-TB) include contact with a patient with MDR-TB, origin from an endemic region, or failure of therapy with documented supervision. Collaboration with experts was imperative in ensuring appropriate patient care.

A 39-Year-Old Pregnant Woman with Pulmonary Emboli on Long Term Anticoagulation.

We present the case of a 39-year-old pregnant woman with Klippel-Trenaunay syndrome (KTS). We demonstrate the risks of multiple, co-existing pro-thrombotic states (pregnancy, KTS), discuss complications of KTS (deep venous thromboembolisms and pulmonary emboli) and highlight general and disease-specific preventive measures against venous thromboembolic events (VTE). KTS is a rare condition and it's co-existence with pregnancy and VTEs is rarer still.