Developmental regulation of matrix metalloproteinases in response to multi-factorial, severe TBI injuries during immaturity.

INTRODUCTION: A striking pattern in young children after severe TBI is when the entire cortical ribbon displays tissue damage: hemispheric hypodensity (HH). HH is often a result of abusive head trauma (AHT). We previously reported a model of HH in a gyrencephalic species where a combination of injuries consisting of 1) cortical impact, 2) midline shift, 3) subdural hematoma/subarachnoid hemorrhage, 4) traumatic seizures, and 5) brief apnea and hypoventilation, resulted in extensive, hypoxic-ischemic type injury. Importantly, this mechanism closely resembles that seen in children, with relative sparing of the contralateral cortex, thus, ruling out a pure asphyxia mechanism. In this model, piglets of similar developmental stage to human toddlers (postnatal day 30, PND30) have extensive hypoxic-ischemic damage to the cortical ribbon with sparing of the contralateral hemisphere and deep gray matter areas. However, piglets of similar developmental stage to human infants (postnatal day 7, PND7) have less hypoxic-ischemic damage that is notably bilateral and patchy. We therefore sought to discover whether the extensive tissue damage observed in PND30 was due to a greater upregulation of matrix metalloproteinases (MMPs). MATERIALS AND METHODS: In PND 7 or PND 30 piglets receiving AHT injuries (cortical impact, midline shift, subdural hematoma/subarachnoid hemorrhage, traumatic seizures, and brief apnea and hypoventilation) or a sham injury, the pattern of albumin extravasation and MMP-9 upregulation throughout the brain was determined via immunohistochemistry, brain tissue adjacent to the cortical impact where the tissue damage spreads was collected for Western blots, and the gelatinase activity was determined over time in peripheral plasma. EEG was recorded and piglets survived up to 24 hours after injury administration. RESULTS: The pattern of albumin extravasation, indicating vasogenic edema, as well as increase in MMP-9, were both present at the same areas of hypoxic-ischemic tissue damage. Evidence from immunohistochemistry, western blot, and zymogens demonstrate that MMP- 2,- 3 or -9 are constitutively expressed during immaturity and are not different between developmental stages; however, active forms are upregulated in PND30 but not PND7 after in response to AHT model injuries. Furthermore, peripheral active MMP-9 was downregulated after model injuries in PND7. CONCLUSIONS: This differential response to AHT model injuries might confer protection to the PND7 brain. Additionally, we find that immature gyrencephalic species have a greater baseline and array of MMP's than previously demonstrated in rodent species. Treatment with an oral or intravenous broad-spectrum matrix metalloproteinase inhibitor might reduce the extensive spread of injury in PND30, but the exposure to metalloproteinase inhibitors must be acute as to not interfere with the homeostatic role of matrix metalloproteinases in normal postnatal brain development and plasticity as well as post-injury synaptogenesis and tissue repair.

Brief apnea with hypoventilation reduces seizure duration and shifts seizure location for several hours in a model of severe traumatic brain injury.

OBJECTIVE: Seizures can be difficult to control in infants and toddlers. Seizures with periods of apnea and hypoventilation are common following severe traumatic brain injury (TBI). We previously observed that brief apnea with hypoventilation (A&H) in our severe TBI model acutely interrupted seizures. The current study is designed to determine the effect of A&H on subsequent seizures and whether A&H has potential therapeutic implications. METHODS: Piglets (1 week or 1 month old) received multifactorial injuries: cortical impact, mass effect, subdural hematoma, subarachnoid hemorrhage, and seizures induced with kainic acid. A&H (1 min apnea, 10 min hypoventilation) was induced either before or after seizure induction, or control piglets received subdural/subarachnoid hematoma and seizure without A&H. In an intensive care unit, piglets were sedated, intubated, and mechanically ventilated, and epidural electroencephalogram was recorded for an average of 18 h after seizure induction. RESULTS: In our severe TBI model, A&H after seizure reduced ipsilateral seizure burden by 80% compared to the same injuries without A&H. In the A&H before seizure induction group, more piglets had exclusively contralateral seizures, although most piglets in all groups had seizures that shifted location throughout the several hours of seizure. After 8-10 h, seizures transitioned to interictal epileptiform discharges regardless of A&H or timing of A&H. SIGNIFICANCE: Even brief A&H may alter traumatic seizures. In our preclinical model, we will address the possibility of hypercapnia with normoxia, with controlled intracranial pressure, as a therapeutic option for children with status epilepticus after hemorrhagic TBI.

Speech Outcomes of Frenectomy for Tongue-Tie Release: A Systematic Review and Meta-Analysis.

OBJECTIVE: Tongue-tie, which is also known as ankyloglossia, is a common condition where the lingual frenulum is unusually tight or short. While most literature investigates the impact of tongue-tie on breastfeeding, recent articles have examined its role in speech production in children. However, these have not previously been reviewed systematically. This study aims to determine the impact of tongue-tie on speech outcomes and assess whether frenectomy can improve speech function. METHODS: In this systematic review, we conducted a comprehensive search of PubMed/MEDLINE, Cochrane Library, Embase, and speechBITE to analyze primary studies investigating the impact of frenectomy for tongue-tie on speech outcomes. We extracted data regarding patient age, male to female ratio, procedure type, follow-up time, and speech outcomes and ran statistical analyses to determine if frenectomy for tongue-tie leads to improvement in speech issues in pediatric patients. Speech outcomes extracted were subjectively measured based on the interpretation of a speech and language pathologist or parent. RESULTS: Our analysis included 10 studies with an average patient age of 4.10 years, and average cohort size of 22.17 patients. Overall, frenectomy for tongue-tie was associated with an improvement in speech articulation (0.78; 95% CI: 0.64-0.87; P < .01). Increasing patient age was found to be negatively correlated with post-frenectomy speech outcomes (P = .01). However, this relationship disappeared in the adjusted model. CONCLUSION: Overall, we conclude that frenectomy is a suitable treatment to correct speech issues in select patients with tongue-tie if caught early in childhood. Despite the limited investigations around speech outcomes post-frenectomy, these results are informative to providers treating tongue-tie.