Subtemporal Decompression in Resistant Slit Ventricle Syndrome in Children: An Observational Study and Survival Analysis.

INTRODUCTION: Slit ventricle syndrome (SVS) remains a challenging problem in the early-shunted paediatric population. Various surgical and non-surgical treatments have been devised for this condition. However, there is currently no gold standard for its optimal management. Among various treatment modalities, subtemporal decompression (STD) is often performed as a last resort. We present our experience of STD in paediatric patients with SVS in whom initial treatment with programmable valves and anti-syphon device were not successful. METHODS: This is a single-centre retrospective observational study and survival analysis. Patients who underwent STD for SVS were included. Pre- and post-operative imaging data and clinical outcomes were collected. RESULTS: There were 20 patients (12 M, 8 F) with a mean age of 9 years (SD: 4) at first STD. 90% (n = 18) of patients had multiple shunt revisions pre-STD. At first STD, 70% (n = 14) and 30% (n = 6) of patients had unilateral or bilateral STD, respectively. STD led to a reduction in the frequency of shunt revisions in 60% (n = 12) of patients. The median time required before further STD, shunt surgery, or cranial vault surgery was 14 months. The median time before a further STD was required (either revision or contralateral side) was 89 months. At a median follow-up of 66.5 months (range: 1-159), 65% (n = 13) of patients had improvement in symptoms. CONCLUSIONS: A large proportion of patients with persistent SVS symptoms, refractory to multiple shunt revisions, benefitted from STD in combination with shunt optimization. It was also safe and well-tolerated. Therefore, in patients who have multiple failed shunts, STD may reduce the morbidity associated with further shunt revisions and can significantly improve symptomatology.

Care and three-year outcomes of children with Benign Epilepsy with Centro-Temporal Spikes in England.

PURPOSE: Benign Epilepsy with Centro-Temporal Spikes (BECTS) is a pediatric epilepsy with typically good seizure control. Although BECTS may increase patients' risk of developing neurological comorbidities, their clinical care and short-term outcomes are poorly quantified. METHODS: We retrospectively assessed adherence to National Institute for Health and Care Excellence (NICE) guidelines relating to specialist referral, electroencephalogram (EEG) conduct and annual review in the care of patients with BECTS, and measured their seizure, neurodevelopmental and learning outcomes at three years post-diagnosis. RESULTS: Across ten centers in England, we identified 124 patients (74 male) diagnosed with BECTS between 2015 and 2017. Patients had a mean age at diagnosis of 8.0 (95% CI = 7.6-8.4) years. 24/95 (25%) patients were seen by a specialist within two weeks of presentation; 59/100 (59%) received an EEG within two weeks of request; and 59/114 (52%) were reviewed annually. At three years post-diagnosis, 32/114 (28%) experienced ongoing seizures; 26/114 (23%) had reported poor school progress; 15/114 (13%) were diagnosed with a neurodevelopmental disorder (six autism spectrum disorder, six attention-deficit/hyperactivity disorder); and 10/114 (8.8%) were diagnosed with a learning difficulty (three processing deficit, three dyslexia). Center-level random effects models estimated neurodevelopmental diagnoses in 9% (95% CI: 2-16%) of patients and learning difficulty diagnoses in 7% (95% CI: 2-12%). CONCLUSIONS: In this multicenter work, we found variable adherence to NICE guidelines in the care of patients with BECTS and identified a notable level of neurological comorbidity. Patients with BECTS may benefit from enhanced cognitive and behavioral assessment and monitoring.

Management and outcomes of intracranial fungal infections in children and adults in Africa: a scoping review protocol.

INTRODUCTION: The protocol presents the methodology of a scoping review that aims to synthesise contemporary evidence on the management and outcomes of intracranial fungal infections in Africa. METHODS AND ANALYSIS: The scoping review will be conducted in accordance with the Arksey and O'Malley's framework. The research question, inclusion and exclusion criteria and search strategy were developed based on the Population, Intervention, Comparator, Outcome framework. A search will be conducted in electronic bibliographic databases (Medline (OVID), Embase, African Journals Online, Cochrane Library and African Index Medicus). No restrictions on language or date of publication will be made. Quantitative and qualitative data extracted from included articles will be presented through descriptive statistics and a narrative description. ETHICS AND DISSEMINATION: This study protocol does not require ethical approval. Findings will be reported in a peer-reviewed medical journal and presented at local, regional, national and international conferences.

Current Attitudes Toward Neuroanatomy: A Comparative Cross-Sectional Survey of Neurosurgeons from the United Kingdom and Worldwide.

OBJECTIVE: How attitudes toward neuroanatomy and preferences of studying resources vary among neurosurgeons is unknown. The impact of the coronavirus disease 2019 (COVID-19) pandemic on anatomy learning habits is also yet to be elucidated. In this study, we explore these objectives, to guide the development of future neurosurgeon-tailored anatomy education and resources. METHODS: This was a 2-stage, cross-sectional study design comprising a local pilot survey followed by a structured 17-item questionnaire, distributed to both neurosurgical trainees and consultants. Grade and nationality differences in sentiment agreement were statistically compared. RESULTS: A total of 365 responses were received from 32 countries (overall response rate, 23.2%). Neuroanatomy is highly regarded among most neurosurgeons and takes a central role in their professional identity. Yet, 69% of neurosurgeons wanted to spend more time learning. Common study prompts included perceived operative complexity, lack of familiarity and teaching. Financial barriers and motivation were obstacles limiting neuroanatomy learning, more so among trainee neurosurgeons, with personal commitment barriers significantly varying with geographic location. Surgical relevance, accessibility, and image quality were important factors when selecting anatomy resources, with cost and up-to-datedness being important for juniors. The COVID-19 pandemic saw a shift toward virtual resources, particularly affecting United Kingdom-based trainees. CONCLUSIONS: Although neuroanatomy is well regarded, barriers exist that impede further neuroanatomy learning. Neurosurgical training programs should tailor anatomy education according to the seniority and background of their residents. Furthermore, resources that are surgically relevant and accessible and are of high image quality are more likely to be better used.

Novel Anticoagulants and Hip Fractures in the Elderly.

Introduction Early surgery is recommended in hip fractures to reduce morbidity and mortality. Surgery is often delayed in patients on novel direct oral anticoagulants (DOACs). The purpose of our study was to investigate the impact of DOACs on patients with hip fractures. Methods A retrospective comparative analysis was performed. A total of 766 patients presented with neck of femur fractures in the study period. Patients under the age of 60, those managed conservatively and those on alternative anticoagulation (including warfarin, clopidogrel and aspirin) were excluded. Forty-seven (6.1%) patients were on DOACs, to which a group of 47 patients was matched for age, gender, fracture type and intervention to minimise confounding. Primary outcome data on time to surgery (TTS), pre-/postoperative haemoglobin, haemoglobin drop, length of stay (LOS) and 30-day mortality were collected, as well as secondary outcome data on blood transfusion and wound complications. The Charlson Comorbidity Index (CCI) was calculated for all patients. Results The mean Charlson Comorbidity Index was significantly increased in the DOAC group (p<0.0001). The mean time to surgery was 49.5 hours in the DOAC group versus 31.3 hours in the control group (p=0.0002). Haemoglobin drop for DOAC patients was 16.9 g/L and 15.9 g/L for control patients (p=0.6). Similarly, no significant increase in transfusion was required (p=0.74). Six DOAC patients and two control group patients died within 30 days of surgery (p=0.13). Wound complications were seen in five (10.6%) patients on DOAC and two (4.2%) patients in the control group (p=0.02). Conclusion The results demonstrate statistically significantly higher comorbidities, delay in surgery and higher wound complications in patients on DOAC but no significant difference in haemoglobin drop, blood transfusion and mortality.

Pharmacological venous thromboembolism prophylaxis in elective cranial surgery: a systematic review of time of initiation, regimen and duration.

INTRODUCTION: Pharmacological prophylaxis of venous thromboembolism (VTE) requires nuanced decision-making to balance the risk of VTE against haemorrhage. This problem is compounded in neurosurgical patients, in whom postoperative intracranial haemorrhage (ICH) may be catastrophic, compared to non-neuraxial bleeding in other types of surgery. Current major guidelines recommend caution when using pharmacological prophylaxis in elective cranial surgery, but incorporate low-quality evidence and lack precise guidance on timing and duration of anticoagulation. METHODS: We aimed to answer the following questions for patients undergoing elective cranial surgery: (1) when is the optimal time to initiate postoperative anticoagulation, and (2) how long should postoperative anticoagulation be continued for? In this systematic review, we screened randomised and non-randomised studies reporting original data on pharmacological VTE prophylaxis in elective cranial surgery. Outcomes of interest were VTE and ICH. RESULTS: Three retrospective, single-centre observational studies met eligibility criteria, with a total of 923 participants. Meta-analysis was not performed due to a high risk of bias across all studies. Through narrative synthesis, we found that patients who developed VTE were significantly more likely to receive their first postoperative dose at a later time (mean: 144 vs. 29 h, p = .04). Shorter courses of anticoagulation (<7 days) were associated with significantly lower ICH rates (p = .03) compared to longer courses (>21 days). CONCLUSION: The limited evidence favours earlier initiation and shorter courses of thromboprophylactic anticoagulation. These findings are specific to patients undergoing surgery for meningioma or glioma and may not apply to other populations. Randomised controlled trials or robustly designed observational studies are necessary to establish a clearer evidence base.

Proportion of resected seizure onset zone contacts in pediatric stereo-EEG-guided resective surgery does not correlate with outcome.

OBJECTIVE: We aimed to determine whether the proportion of putative seizure onset zone (SOZ) contacts resected associates with seizure outcome in a cohort of children undergoing stereoelectroencephalography (SEEG)-guided resective epilepsy surgery. METHODS: Patients who underwent SEEG-guided resective surgery over a six-year period were included. The proportion of SOZ contacts resected was determined by co-registration of pre- and post-operative imaging. Outcome was classified as seizure free (SF, Engel class I) or not seizure-free (NSF, Engel class II-IV) at last clinical follow-up. RESULTS: Twenty-nine patients underwent resection of whom 22 had sufficient imaging data for analysis (median age at surgery of 10 years, range 5-18). Fifteen (68.2%) were SF at median follow-up of 19.5 months (range 12-46). On univariate analysis, histopathology, was the only significant factor associated with SF (p < 0.05). The percentage of defined SOZ contacts resected ranged from 25-100% and was not associated with SF (p = 0.89). In a binary logistic regression model, it was highly likely that histology was the only independent predictor of outcome. CONCLUSIONS: The percentage of SOZ contacts resected was not associated with SF in children undergoing SEEG-guided resective epilepsy surgery. SIGNIFICANCE: Factors such as spatial organisation of the epileptogenic zone, neurophysiological biomarkers and the prospective identification of pathological tissue may therefore play an important role.

Management and Outcomes of Low-Grade Gliomas in Africa: A Scoping Review Protocol.

BACKGROUND: Over the last decade, many advancements have been made in the management of low-grade gliomas (LGGs). Overall survival outcomes are correlated with factors such as postoperative residual volumes and specific tumor biomolecular profiles such as IDH mutation status. It is unclear whether these advancements have benefited LGG patients in Africa. This scoping review protocol outlines how the authors will evaluate the epidemiology, presentations, management and outcomes of LGGs in Africa. METHODS: MEDLINE, Embase and African Journals Online will be searched from database inception to date in order to identify the relevant studies. Patients of all ages with histologically and/or radiologically confirmed LGGs that were managed in an African country will be included. Surgical and chemoradiation management of LGG tumours will be considered. Original research, reviews, commentaries, editorials and case reports will be included. RESULTS: Primary outcomes of the review will include LGG management, morbidity and mortality. Secondary outcomes include epidemiology and recurrence of LGGs. DISCUSSION: This scoping review will be the first to evaluate the current landscape of LGG management and outcomes in Africa, highlighting pertinent themes that may be used to guide further research as well as health system strengthening efforts by policymakers and stakeholders. SCOPING REVIEW REGISTRATION: The protocol has been registered on the Open Science Framework (OSF; registration link: https://doi.org/10.17605/OSF.IO/E732G). HIGHLIGHTS: LGGs account for 17% to 22% of total brain tumours and have a median survival time between 5.6 and 13.3 years.Despite many recent advancements in the management of LGGs, there is a paucity in the data within the African landscape.This scoping review will be the first to evaluate the current landscape of LGG management and outcomes in Africa, highlighting pertinent themes that may be used to guide further research and policymaking efforts.

Management and outcomes of low-grade gliomas in Africa: A scoping review.

INTRODUCTION: Despite recent advancements in the management of low-grade gliomas (LGGs), there is a paucity in the data within the African landscape. We aim to evaluate the epidemiology, management, and outcomes of LGGs in Africa. METHODS: Systematic searches of MEDLINE, Embase and African Journals Online were performed from database inception to January 27, 2021, for studies reporting on LGGs in Africa. Pooled statistics were calculated using measures of central tendency and spread. RESULTS: 554 unique studies were identified, of which 25 were included. The mean age of patients was 15.7 years (95% confidence interval (CI): 11.8-19.6) and 56.4% were male (95% CI: 55.6-62.6%). Most patients had solitary lesions (86.0%, 95% CI: 82.8-89.1%) located in the infratentorial region (71.6%, 95% CI: 66.1-77.1%). Most LGGs received histopathological diagnosis (71.7%, 95% CI: 69.2-74.2%) and astrocytoma was the most common type (81.1%, 95% CI: 78.5-83.7%). 37 patients had awake surgery (3.1%, 95% CI: 2.0-4.0%) and there were no reports of molecular pathology testing, intraoperative neuroimaging, or 5-aminolevulinic acid. Gross total resection was achieved in 74.8% (95% CI: 69.6-80.0%) and there was a recurrence rate of 1.7% (95% CI: 0.9-2.4%), with a mean follow-up of 19.4 months (95% CI: 6.9-31.9). CONCLUSION: LGGs are underreported in Africa. We found a lag in the uptake of techniques established in high-income countries for improving patient outcomes. Future efforts will require further training and funding in molecular pathology testing and advanced surgical adjuncts.

Intracranial neuromodulation with deep brain stimulation and responsive neurostimulation in children with drug-resistant epilepsy: a systematic review.

OBJECTIVE: In children with drug-resistant epilepsy (DRE), resective, ablative, and disconnective surgery may not be feasible or may fail. Neuromodulation in the form of deep brain stimulation (DBS) and responsive neurostimulation (RNS) may be viable treatment options, however evidence for their efficacies in children is currently limited. This systematic review aimed to summarize the literature on DBS and RNS for the treatment of DRE in the pediatric population. Specifically, the authors focused on currently available data for reported indications, neuromodulation targets, clinical efficacy, and safety outcomes. METHODS: PRISMA guidelines were followed throughout this systematic review (PROSPERO no. CRD42020180669). Electronic databases, including PubMed, Embase, Cochrane Library, OpenGrey, and CINAHL Plus, were searched from their inception to February 19, 2021. Inclusion criteria were 1) studies with at least 1 pediatric patient (age < 19 years) who underwent DBS and/or RNS for DRE; and 2) retrospective, prospective, randomized, or nonrandomized controlled studies, case series, and case reports. Exclusion criteria were 1) letters, commentaries, conference abstracts, and reviews; and 2) studies without full text available. Risk of bias of the included studies was assessed using the Cochrane ROBINS-I (Risk of Bias in Non-randomised Studies - of Interventions) tool. RESULTS: A total of 35 studies were selected that identified 72 and 46 patients who underwent DBS and RNS, respectively (age range 4-18 years). Various epilepsy etiologies and seizure types were described in both cohorts. Overall, 75% of patients had seizure reduction > 50% after DBS (among whom 6 were seizure free) at a median (range) follow-up of 14 (1-100) months. In an exploratory univariate analysis of factors associated with favorable response, the follow-up duration was shorter in those patients with a favorable response (18 vs 33 months, p < 0.05). In the RNS cohort, 73.2% of patients had seizure reduction > 50% after RNS at a median (range) follow-up of 22 (5-39) months. On closer inspection, 83.3% of patients who had > 50% reduction in seizures actually had > 75% reduction, with 4 patients being seizure free. CONCLUSIONS: Overall, both DBS and RNS showed favorable response rates, indicating that both techniques should be considered for pediatric patients with DRE. However, serious risks of overall bias were found in all included studies. Many research needs in this area would be addressed by conducting high-quality clinical trials and establishing an international registry of patients who have undergone pediatric neuromodulation, thereby ensuring robust prospective collection of predictive variables and outcomes.

Survey Fatigue During the COVID-19 Pandemic: An Analysis of Neurosurgery Survey Response Rates.

Background: The COVID-19 pandemic has caused a surge in research activity while restricting data collection methods, leading to a rise in survey-based studies. Anecdotal evidence suggests this increase in neurosurgical survey dissemination has led to a phenomenon of survey fatigue, characterized by decreased response rates and reducing the quality of data. This paper aims to analyze the effect of COVID-19 on neurosurgery surveys and their response rates, and suggest strategies for improving survey data collection. Methods: A search was conducted on March 20, 2021, on Medline and EMBASE. This included the terms "neurosurgery," "cranial surgery," "spine surgery," and "survey" and identified surveys written in English, on a neurosurgical topic, distributed to neurosurgeons, trainees, and medical students. Results were screened by two authors according to these inclusion criteria, and included articles were used for data extraction, univariable, and bivariable analysis with Fisher's exact-test, Wilcoxon rank-sum test, and Spearman's correlation. Results: We included 255 articles in our analysis, 32.3% of which were published during the COVID-19 pandemic. Surveys had an average of 25.6 (95% CI = 22.5-28.8) questions and were mostly multiple choice (78.8%). They were disseminated primarily by email (75.3%, 95% CI = 70.0-80.6%) and there was a significant increase in dissemination via social media during the pandemic (OR = 3.50, 95% CI = 1.30-12.0). COVID-19 surveys were distributed to more geographical regions than pre-pandemic surveys (2.1 vs. 1.5, P = 0.01) and had higher total responses (247.0 vs. 206.4, P = 0.01), but lower response rates (34.5 vs. 51.0%, P < 0.001) than pre-COVID-19 surveys. Conclusion: The rise in neurosurgical survey distribution during the COVID-19 pandemic has led to survey fatigue, reduced response rates, and data collection quality. We advocate for population targeting to avoid over-researching, collaboration between research teams to minimize duplicate surveys, and communication with respondents to convey study importance, and we suggest further strategies to improve response rates in neurosurgery survey data collection.

Neurosurgical experience of managing optic pathway gliomas.

BACKGROUND: Optic pathway gliomas (OPGs), also known as visual pathway gliomas, are debilitating tumors that account for 3-5% of all pediatric brain tumors. They are most commonly WHO grade 1 pilocytic astrocytomas and frequently occur in patients with neurofibromatosis type 1. The location of these tumors results in visual loss and blindness, endocrine and hypothalamic dysfunction, hydrocephalus, and premature death. Their involvement of the visual pathways and proximity to other eloquent brain structures typically precludes complete resection or optimal radiation dosing without incurring significant neurological injury. There are various surgical interventions that can be performed in relation to these lesions including biopsy, cerebrospinal fluid diversion, and partial or radical resection, but their role is a source of debate. This study catalogues our surgical experience and patient outcomes in order to support decision-making in this challenging pathology. METHODS: A retrospective review of all cases of OPGs treated in a single center from July 1990 to July 2020. Data was collected on patient demographics, radiographic findings, pathology, and management including surgical interventions. Outcome data included survival, visual function, endocrine, and hypothalamic dysfunction. RESULTS: One hundred twenty-one patients with OPG were identified, and 50 of these patients underwent a total of 104 surgical procedures. These included biopsy (31), subtotal or gross total resection (20 operations in 17 patients), cyst drainage (17), Ommaya reservoir insertion (9), or cerebrospinal fluid diversion (27). During the study period, there was 6% overall mortality, 18% hypothalamic dysfunction, 20% endocrine dysfunction, and 42% had some cognitive dysfunction. At diagnosis 75% of patients had good or moderate visual function in at least one eye, and overall, this improved to 83% at the end of the study period. In comparison the worst eye had good or moderate visual function in 56%, and this reduced to 53%. Baseline and final visual function were poorer in patients who had a surgical resection, but improvements in vision were still found-particularly in the best eye. DISCUSSION/CONCLUSION: OPG are debilitating childhood tumor that have lifelong consequences in terms of visual function and endocrinopathies/hypothalamic dysfunction; this can result in substantial patient morbidity. Decisions regarding management and the role of surgery in this condition are challenging and include cerebrospinal fluid diversion, biopsy, and in highly select cases cystic decompression or surgical resection. In this paper, we review our own experience, outcomes, and surgical philosophy.

Impact of the Coronavirus (COVID-19) pandemic on surgical practice - Part 2 (surgical prioritisation).

The Coronavirus (COVID-19) Pandemic represents a once in a century challenge to human healthcare with over 4.5 million cases and over 300,000 deaths thus far. Surgical practice has been significantly impacted with all specialties writing guidelines for how to manage during this crisis. All specialties have had to triage the urgency of their daily surgical procedures and consider non-surgical management options where possible. The Pandemic has had ramifications for ways of working, surgical techniques, open vs minimally invasive, theatre workflow, patient and staff safety, training and education. With guidelines specific to each specialty being implemented and followed, surgeons should be able to continue to provide safe and effective care to their patients during the COVID-19 pandemic. In this comprehensive and up to date review we assess changes to working practices through the lens of each surgical specialty.

Impact of the Coronavirus (COVID-19) pandemic on surgical practice - Part 1.

The Coronavirus (COVID-19) pandemic has resulted in over 4.5 million confirmed cases and over 300,000 deaths. The impact of COVID-19 on surgical practice is widespread, ranging from workforce and staffing issues, procedural prioritisation, viral transmission risk intraoperatively, changes to perioperative practice and ways of working alongside the impact on surgical education and training. Whilst there has been a growing literature base describing the early clinical course of COVID-19 and on aspects of critical care related to treating these patients, there has been a dearth of evidence on how this pandemic will affect surgical practice. This paper seeks to review the current evidence and offers recommendations for changes to surgical practice to minimise the effect of the COVID-19 pandemic.

Evidence based management guideline for the COVID-19 pandemic - Review article.

COVID-19 has now been declared a pandemic. To date, COVID-19 has affected over 2.5 million people worldwide, resulting in over 170,000 reported deaths. Numerous preventative strategies and non-pharmaceutical interventions have been employed to mitigate the spread of disease including careful infection control, the isolation of patients, and social distancing. Management is predominantly focused on the provision of supportive care, with oxygen therapy representing the major treatment intervention. Medical therapy involving corticosteroids and antivirals have also been encouraged as part of critical management schemes. However, there is at present no specific antiviral recommended for the treatment of COVID-19, and no vaccine is currently available. Despite the strategic implementation of these measures, the number of new reported cases continues to rise at a profoundly alarming rate. As new findings emerge, there is an urgent need for up-to-date management guidelines. In response to this call, we review what is currently known regarding the management of COVID-19, and offer an evidence-based review of current practice.

World Health Organization declares global emergency: A review of the 2019 novel coronavirus (COVID-19).

An unprecedented outbreak of pneumonia of unknown aetiology in Wuhan City, Hubei province in China emerged in December 2019. A novel coronavirus was identified as the causative agent and was subsequently termed COVID-19 by the World Health Organization (WHO). Considered a relative of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), COVID-19 is caused by a betacoronavirus named SARS-CoV-2 that affects the lower respiratory tract and manifests as pneumonia in humans. Despite rigorous global containment and quarantine efforts, the incidence of COVID-19 continues to rise, with 90,870 laboratory-confirmed cases and over 3,000 deaths worldwide. In response to this global outbreak, we summarise the current state of knowledge surrounding COVID-19.

Resistant Pseudomeningocele following Craniotomy for Non-Traumatic Acute Intracranial Haematoma in Very Young Children: Report of Four Cases.

BACKGROUND: The incidence of non-traumatic intracranial haemorrhage among neonates is less than among adults. However, the outcomes are generally poor, with high rates of morbidity and mortality. Non-traumatic intracranial haemorrhage can cause a sudden increase in intracranial pressure, requiring emergency craniotomy for evacuation. METHODS: We report 4 cases following craniotomy for non-traumatic acute intracranial haematoma in very young children. The surgical technique and postoperative course are discussed, with emphasis on dural repair to avoid resistant pseudomeningocele. RESULTS: Despite successful management of the acutely raised intracranial pressure, all patients afterwards developed tense pseudomeningoceles and required formal dural repair. This led to a change in institutional practice and modifications to the surgical technique. CONCLUSION: The authors highlight the postoperative occurrence of resistant pseudomeningoceles in young children after clot evacuations and leaving the dura open. They describe the surgical procedures to avoid these pseudomeningoceles.

Antigen presenting cells (APCs) from thermally injured and/or septic rats modulate CD4+ T cell responses of naive rat.

Regulation of immune response is marked by complex interactions among the cells that recognize and present antigens. Antigen presenting cells (APCs), the antigen presenting cell component of the innate immune response plays an important role in effector CD4+ T cell response. Thermal injury and/or superimposed sepsis in rats' leads to suppressed CD4+ T cell functions. We investigated modulations of CD4+ T cell function by APCs (purified non-T cells) from thermally injured and/or septic rats. Rats were subjected to 30% total body surface area scald burn or exposed to 37 degrees C water (Sham burn) and sepsis was induced by cecal-ligation and puncture (CLP) method. At day 3 post-injury animals were sacrificed and CD4+ T cells and APCs from mesenteric lymph nodes (MLN) were obtained using magnetic microbead isolation procedure. APCs from injured rats were co-cultured with sham rat MLN CD4+ T cells and proliferative responses (thymidine incorporation), phenotypic changes (Flow cytometry), IL-2 production (ELISA) and CTLA-4 mRNA (RT-PCR) were determined in naive rat CD4+ T cells. The data indicate that APCs from thermally injured and/or septic rats when co-cultured with CD4+ T cells suppressed CD4+ T cell effector functions. This lack of CD4+ T cell activation was accompanied with altered co-stimulatory molecules, i.e., CD28 and/or CTLA-4 (CD152). In conclusion, our studies indicated that defective APCs from thermally injured and/or septic rats modulate CD4+ T cell functions via changes in co-stimulatory molecules expressed on naive CD4+ T cells. This altered APC: CD4+ T cell interaction leads to suppressed CD4+ T cell activation of healthy animals.

Mechanisms of postburn intestinal barrier dysfunction in the rat: roles of epithelial cell renewal, E-cadherin, and neutrophil extravasation.

OBJECTIVE: Our group has previously shown that the intestinal epithelium exhibits increased postburn barrier permeability and bacterial translocation associated with deranged neutrophil activity. The purpose of this investigation is to explore possible underlying intestinal structural mechanisms, leading to those functional changes with emphasis on (1) neutrophil influx and extravasation in the intestinal lamina propria 1-3 days after burn and (2) enterocyte proliferation, migration, apoptosis, and E-cadherin junctional epithelium levels 3 days after burn. DESIGN: Freshly isolated ileum specimens were quick frozen, then cut by a cryostat into 30-micron-thick sections. Sections from day 1 postburn rats were immunostained with (1) anti-granulocyte or anti-elastase antibodies to assess neutrophil influx or (2) combined anti-granulocyte and anti-von Willebrand factor double immunolabeling to compare levels of neutrophil extravasation. Sections from day 3 postburn rats were immunostained with (1) bromodeoxyuridine immunohistochemistry 1, 3, 6, or 18 hrs after bromodeoxyuridine injection to assess enterocyte proliferation and migration, (2) cytokeratin-18 M30-immunohistochemistry to compare levels of enterocyte apoptosis, and (3) E-cadherin immunohistochemistry to compare junctional E-cadherin integrity. Ileal myeloperoxidase activity and bacterial translocation of Enterococcus faecalis were assessed biochemically and by E. faecalis-specific bacterial cultures, respectively, in day 3 postburn rats. SETTING: : Research laboratories in a medical center and an academic institution. SUBJECTS: Male Sprague-Dawley rats given sham treatment or treatment as a burn model with full-thickness skin scald over 30% total body surface area. CONCLUSIONS: We report (1) increased levels of neutrophil influx and extravasation in villi lamina propriae, including elastase-positive cells (postburn day 1), (2) heightened levels of intestinal myeloperoxidase activity (postburn day 3), (3) decreased levels of epithelial cell proliferation, migration, and E-cadherin (postburn day 3), and (4) increased enterocyte apoptosis and E. faecalis bacterial translocation (postburn day 3). Based on these structural and functional abnormalities, we propose a mechanism for burn injury-related intestinal barrier dysfunction that includes increased trans- and para-cellular leakage caused by impaired enterocyte renewal and decreased junctional E-cadherin levels subsequent to increased neutrophil influx and extravasation within the villus lamina propria microenvironment.