IL-6 Inhibition Reduces Neuronal Injury in a Murine Model of Ventilator-induced Lung Injury.

Mechanical ventilation is a known risk factor for delirium, a cognitive impairment characterized by dysfunction of the frontal cortex and hippocampus. Although IL-6 is upregulated in mechanical ventilation-induced lung injury (VILI) and may contribute to delirium, it is not known whether the inhibition of systemic IL-6 mitigates delirium-relevant neuropathology. To histologically define neuropathological effects of IL-6 inhibition in an experimental VILI model, VILI was simulated in anesthetized adult mice using a 35 cc/kg tidal volume mechanical ventilation model. There were two control groups, as follow: 1) spontaneously breathing or 2) anesthetized and mechanically ventilated with 10 cc/kg tidal volume to distinguish effects of anesthesia from VILI. Two hours before inducing VILI, mice were treated with either anti-IL-6 antibody, anti-IL-6 receptor antibody, or saline. Neuronal injury, stress, and inflammation were assessed using immunohistochemistry. CC3 (cleaved caspase-3), a neuronal apoptosis marker, was significantly increased in the frontal (P < 0.001) and hippocampal (P < 0.0001) brain regions and accompanied by significant increases in c-Fos and heat shock protein-90 in the frontal cortices of VILI mice compared with control mice (P < 0.001). These findings were not related to cerebral hypoxia, and there was no evidence of irreversible neuronal death. Frontal and hippocampal neuronal CC3 were significantly reduced with anti-IL-6 antibody (P < 0.01 and P < 0.0001, respectively) and anti-IL-6 receptor antibody (P < 0.05 and P < 0.0001, respectively) compared with saline VILI mice. In summary, VILI induces potentially reversible neuronal injury and inflammation in the frontal cortex and hippocampus, which is mitigated with systemic IL-6 inhibition. These data suggest a potentially novel neuroprotective role of systemic IL-6 inhibition that justifies further investigation.

Eyebrow supraorbital keyhole craniotomy for olfactory groove meningiomas with endoscope assistance: case series and systematic review of extent of resection, quantification of postoperative frontal lobe injury, anosmia, and recurrence.

BACKGROUND: Olfactory groove meningiomas (OGMs) are commonly treated with open craniotomy. Endonasal approaches have also been described. OBJECTIVE: To present clinical and radiographic outcomes for the minimally invasive eyebrow incision supraorbital keyhole approach with endoscopic assistance for OGMs. METHODS: We performed a retrospective single-center cohort study and a systematic literature review. RESULTS: Fifteen patients were identified, all with Grade I meningiomas. Radiographic gross total resection of enhancing tumor was achieved in all patients. Mean frontal lobe fluid-attenuated inversion recovery volume decreased from 11.1 ± 18.3 cm3 preoperatively to 9.9 ± 11.4 cm3 immediately postoperatively, and there was minimal new restricted diffusion (3.2 ± 2.2 cm3; max 7.5 cm3). Median length of stay was 3 days (range 2-8). Vision was improved in 4 (80%) and stable in 1 (20%) of 5 patients with a preoperative deficit. New postoperative anosmia occurred in 3 (23%) of 13 patients with any preoperative olfaction. All patients were satisfied with their cosmetic result at 3 months. After a median follow-up of 32.2 months, there were 2 (13.3%) asymptomatic radiographic recurrences, 1 treated with radiosurgery and the other with endoscopic endonasal approach (EEA). No patients required further craniotomy. Systematic review revealed the present series to be the largest to date reporting disaggregated outcomes for the eyebrow approach to OGM. CONCLUSION: The eyebrow incision supraorbital keyhole craniotomy with endoscopic assistance is a safe and effective approach to OGM with tumor control rates similar to more invasive open approaches and better than the endonasal approach. Rates of frontal lobe injury, CSF leak and anosmia are comparatively low.

Activation of the Nrf2-ARE signal pathway after blast induced traumatic brain injury in mice.

Background: Treatment of blast-induced traumatic brain injury (bTBI) has been hindered. Previous studies have demonstrated that oxidative stress may contribute to the pathophysiological process. The nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) signaling pathway exhibits a protective effect after traumatic brain injury (TBI). This study explored whether the Nrf2-ARE pathway was activated in a modified bTBI mouse model. Method: Mice were randomly divided into six groups: the 6 h, 1 d, 3 d, 7 d and 14 d after bTBI groups and a sham group. The protein levels of nuclear Nrf2, heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO1) were detected using western blot, and HO-1 and NQO1 mRNA levels were determined by real-time quantitative polymerase chain reaction. Moreover, HO-1 and Nrf2 were localized using histological staining. Results: The protein level of the Nrf2-ARE pathway in the frontal lobe increased significantly in the 3 d after bTBI. The HO-1 and NQO1 mRNA levels also reached a peak in the frontal lobe 3 d after bTBI. The histological staining demonstrated higher expression of HO-1 in the frontal lobe and hippocampus 3 d after bTBI, when nuclear import of Nrf2 reached a peak in the frontal lobe. Conclusions: bTBI activated the Nrf2-ARE signaling pathway in the brain. The peak activation time in the frontal lobe may be 3 d after injury, and activating the Nrf2 pathway could be a new direction for treatment.

Death Related to Elective Nasal Polypectomy: Case Report.

The investigation of deaths that are suspected to be related to medical therapy present several challenges for a forensic pathologist. We present a case of an otherwise healthy 58-year-old woman with multiple nasal polyps who underwent nasal polypectomy. The operation was initially considered successful. However, the patient had never recovered from general anesthesia and was declared deceased 24 hours after the surgery.The autopsy revealed a basilar subarachnoid hemorrhage. The examination of the basilar skull showed a perforation of approximately 15 by 7 mm in the right cribriform plate. Above the bone perforation, there was a disruption of the dura and a 20-mm-long penetrating wound within the right frontal lobe parenchyma of the brain, with associated intraventricular hemorrhage. The subsequent sectioning of the formalin-fixed brain revealed extensive parenchymal destruction. The cause of death was certified as complications of nasal/sinus surgery, with a perforation of the skull base with hemorrhagic tissue destruction, whereas the manner of death was considered accidental.Common nasal surgical procedures and known complications are discussed.

Penetrating head injury due to angle grinder: an occupational hazard.

Penetrating head injury is a life threatening condition. In the workplace, these are mostly non missile type, low velocity civilian injuries caused by sharp objects. Angle grinders are used to cut stones, metal etc, and cause penetrating head injuries due to shattered rotating discs from the grinder at home and workplaces. We report a series of three cases of penetrating head injuries due to unsafe use of angle grinders. The relevant literature is reviewed and management of such cases is discussed.

Cognitive Outcomes of Patients with Traumatic Bifrontal Contusions.

OBJECTIVES: We aimed to investigate the prevalence and pattern of cognitive dysfunction in patients with traumatic bifrontal contusions and their association with functional outcome. MATERIALS AND METHODS: We prospectively recruited patients with bifrontal contusions in a regional neurosurgical center in Hong Kong over a 2-year period. Functional outcome was assessed by modified Rankin Scale (mRS), and cognitive outcomes were assessed by Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and a comprehensive neuropsychological battery. RESULTS: We recruited 34 patients with traumatic bifrontal contusions over a 2-year period. Nine (26%) patients had craniotomy for evacuation of left or right frontal contusions. Functional outcome using mRS was significantly correlated with cognitive outcomes using MMSE or MoCA. The effect of cognitive outcome using MMSE or MoCA persisted after adjustments of age, sex, admission Glasgow Coma Scale, and surgery. In patients who completed the comprehensive neuropsychological assessments, cognitive impairment in at least one of the neuropsychological tests was noted in 73% of them. CONCLUSIONS: Cognitive dysfunction had a significant impact on functional outcome, and treatment strategy should be developed to minimize them.

Crotalus helleri venom preconditioning reduces postoperative cerebral edema and improves neurological outcomes after surgical brain injury.

INTRODUCTION: Postoperative cerebral edema is a devastating complication in neurosurgical patients. Loss of blood-brain barrier integrity has been shown to lead to the development of brain edema following neurosurgical procedures. The aim of this study was to evaluate preconditioning with Crotalus helleri venom (Cv-PC) as a potential preventive therapy for reducing postoperative brain edema in the rodent SBI model. C. helleri venom is known to contain phospholipase A2 (PLA2), an enzyme upstream to cyclooxygenase-2 (COX-2) in the inflammatory cascade, acts to increase the production of inflammatory mediators, such as prostaglandins. We hypothesize that Cv-PC will downregulate the response of the COX-2 pathway to injury, thereby reducing the inflammatory response and the development of brain edema after SBI. MATERIALS AND METHODS: 75 male Sprague Dawley rats (280-330g) were divided to the following groups-naïve+vehicle, naïve+Cv-PC, sham, vehicle, Cv-PC, Cv-PC+NS398 (COX-2 inhibitor). Vehicle preconditioned and Cv-PC animals received either three daily subcutaneous doses of saline or C. helleri venom at 72h, 48h, and 24h prior to surgery. In Cv-PC+NS398 animals, NS398 was administered intraperitoneally 1h prior to each Cv-PC injection. Sham-operated animals received craniotomy only, whereas SBI animals received a partial right frontal lobectomy. Neurological testing and brain water content were assessed at 24h and 72h after SBI; COX-2 and PGE2 expression was assessed at 24h postoperatively by Western blot and immunohistochemistry, respectively. RESULTS: At 24h after SBI, the vehicle-treated animals were observed to have increased brain water content (83.1±0.2%) compared to that of sham animals (80.2±0.1%). The brain water content of vehicle-treated animals at 72h post-SBI was elevated at 83.3±0.2%. Cv-PC-treated animals with doses of 10% LD50 had significantly reduced brain water content of 81.92±0.7% and 81.82±0.3% at 24h and 72h, respectively, after SBI compared to that of vehicle-treated animals, while Cv-PC with 5% LD50 doses showed brain water content that trended lower but did not reach statistical significance. At 24h and 72h post-SBI, Cv-PC-treated animals had significantly higher neurological score than vehicle-treated animals. The COX-2 over-expression characterized in SBI was attenuated in Cv-PC-treated animals; NS398 reversed the protective effect of Cv-PC on COX-2 expression. Cv-PC tempered the over-expression of the inflammatory marker PGE2. CONCLUSION: Our findings indicate that Cv-PC may provide a promising therapy for reducing postoperative edema and improving neurological function after neurosurgical procedures.

Neural Mechanisms of Temporal Resolution of Attention.

The dynamic nature of the world requires that our visual representations are continuously updated. These representations are more precise if there is a narrow time window over which information is averaged. We assess the neural processes of visual updating by testing patients with lesions including inferior parietal cortex, control patients and healthy adults on a continuous visual monitoring task. In Experiment 1, observers kept track of the changing spatial period of a luminance grating and identified the final spatial period after the stimulus disappeared. Healthy older adults and neurological controls were able to perform better than simulated guesses, but only 3 of 11 patients with damage including parietal cortex were able to reach performance that differed from simulated guesses. The effects were unrelated to lesion size. Poor performance on this task is consistent with an inability to selectively attend to the final moment at which the stimulus was seen. To investigate the temporal limits of attention, we varied the rate of stimulus change in Experiment 2. Performance remained poor for some patients even with slow 2.5 Hz change rates. The performance of 4 patients with parietal damage displayed poor temporal precision, namely recovery of performance with slower rates of change.

Intracranial Foreign Body in a Patient With Paranoid Schizophrenia.

Self-inflicted penetrating head injuries in patients with paranoid schizophrenia are an infrequent phenomenon. The authors report on a psychiatric patient who presented with epistaxis. Computed tomography showed a nail passing from the nasal cavity into the frontal lobe. Given the proximity to large intracranial vessels, a craniotomy was performed and the nail was retracted. The patient later reported having hammered the nail into the nasal cavity with the intention to "kill the voice in my head." Despite use of the latest imaging modalities, metal artifacts may have limited the assessment of vascular involvement. Surgical decision-making preventing secondary damage is crucial in them.

Recombinant Slit2 attenuates neuroinflammation after surgical brain injury by inhibiting peripheral immune cell infiltration via Robo1-srGAP1 pathway in a rat model.

BACKGROUND AND PURPOSE: Peripheral immune cell infiltration to the brain tissue at the perisurgical site can promote neuroinflammation after surgical brain injury (SBI). Slit2, an extracellular matrix protein, has been reported to reduce leukocyte migration. This study evaluated the effect of recombinant Slit2 and the role of its receptor roundabout1 (Robo1) and its downstream mediator Slit-Robo GTPase activating protein 1 (srGAP1)-Cdc42 on peripheral immune cell infiltration after SBI in a rat model. METHODS: One hundred and fifty-three adult male Sprague-Dawley rats (280-350 g) were used. Partial resection of right frontal lobe was performed to induce SBI. Slit2 siRNA was administered by intracerebroventricular injection 24h before SBI. Recombinant Slit2 was injected intraperitoneally 1h before SBI. Recombinant Robo1 used as a decoy receptor was co-administered with recombinant Slit2. srGAP1 siRNA was administered by intracerebroventricular injection 24h before SBI. Post-assessments included brain water content measurement, neurological tests, ELISA, Western blot, immunohistochemistry, and Cdc42 activity assay. RESULTS: Endogenous Slit2 was increased after SBI. Robo1 was expressed by peripheral immune cells. Endogenous Slit2 knockdown worsened brain edema after SBI. Recombinant Slit2 administration reduced brain edema, neurological deficits, and pro-inflammatory cytokines after SBI. Recombinant Slit2 reduced peripheral immune cell markers cluster of differentiation 45 (CD45) and myeloperoxidase (MPO), as well as Cdc42 activity in the perisurgical brain tissue which was reversed by recombinant Robo1 co-administration and srGAP1 siRNA. CONCLUSIONS: Recombinant Slit2 improved outcomes by reducing neuroinflammation after SBI, possibly by decreasing peripheral immune cell infiltration to the perisurgical site through Robo1-srGAP1 mediated inhibition of Cdc42 activity. These results suggest that Slit2 may be beneficial to reduce SBI-induced neuroinflammation.

Lethal hypothermia after firing a suicidal shot to the head in a car.

In suicide cases involving an automobile, the car is mostly used as a tool/instrument for the suicide (intoxication by exhaust fumes, crash against solid objects such as a pylon). However, a car is uncommonly also used only as the location for a suicide. In the present case, a 70-year-old man had been found dead on the passenger seat of his car. According to witnesses, the car had not been parked there at the same time of the previous day. During that period, the weather had been dry, with temperatures ranging from -1° C at night to +5° C during the day. The man had shot himself with a small-caliber revolver (so-called bulldog-revolver) almost horizontally in the left temple (transtemporal shot through the frontal lobes). Obviously, the suicide had retained the capability to act at least for a short time, as the revolver was found under his left bottom. As morphological signs of prolonged agony some findings of hypothermia were observed (e. g. Wischnewski spots of the stomach).

The nature of facilitation and interference in the multilingual language system: insights from treatment in a case of trilingual aphasia.

The rehabilitation study described here sets out to test the premise of Abutalebi and Green's neurocognitive model--specifically, that language selection and control are components of overall cognitive control. We follow a trilingual woman (first language, L1: Amharic; second language, L2: English; third language, L3: French) with damage to the left frontal lobe and left basal ganglia who presented with cognitive control and naming deficits, through two periods of semantic treatment (French, followed by English) to alleviate naming deficits. The results showed that while the participant improved on trained items, she did not show within- or cross-language generalization. In addition, error patterns revealed a substantial increase of interference of the currently trained language into the nontrained language during each of the two treatment phases. These results are consistent with Abutalebi and Green's neurocognitive model and support the claim that language selection and control are components of overall cognitive control.

Detection of hypoxia markers in the cerebellum after a traumatic frontal cortex injury: a human postmortem gene expression analysis.

PURPOSE: The response to traumatic brain injury (TBI) is complex and induces various biological pathways in all brain regions that contribute to bad outcomes. The cerebellar hypoxia after a frontal cortex injury may potentiate the pathophysiological impacts of TBI. Therefore, a gene expression analysis was conducted to determine the influence of hypoxia on TBIs. MATERIAL AND METHODS: Total RNA, including microRNAs, was isolated from the cerebellum of individuals who had died from severe frontal cortex injuries or due to natural causes of death (reference group). RESULTS: From a total of 19,596 genes, an average of 59.56% messenger RNAs (mRNAs) appeared expressed with 42 of them showing significant >2-fold differences of upregulated (n = 18) and downregulated (n = 24) genes. The validity of 14 candidate genes (with low p values and high fold differences or based on cited literature) was confirmed using qRT-PCR (Spearman correlation r(2) = 0.93). Only four genes appeared to be either upregulated (FOSB and IL6) or downregulated (HSD11B1 and HSPA12B). From a total of 667 microRNAs, altogether, 248 microRNAs appeared expressed with 13 of them showing significant differences in the mean gene expression. The combination of two mRNAs (HSPA12B/FOSB or IL6/HSD11B1) or two microRNAs (either miR-138/miR-744 or miR-195/miR-324-5p) completely discriminated both groups, a finding unaltered by potential confounders such as age at biosampling, survival time, and the postmortem interval. CONCLUSIONS: Cerebellar hypoxia markers are important to understand the pathophysiology of TBIs and could be used for therapeutic strategies or forensic purposes, e.g., to assess the severity of a brain injury.

Head Spear Gun Injury: An Atypical Suicide Attempt.

Weapon injuries with spear gun are rare. The aim of this case report is to report the emergency and surgical management when this event occurs. A 35-year-old man attempted suicide with a spear gun. The entry of the shaft was localized through the submental area without an obvious exit point. The projectile passed through the tongue and palatal bone. A tracheotomy was performed. Preoperative cranial computed tomography (CT) showed the harpoon was gone upward through the submental area, the oral cavity, the ethmoid paranasal sinus, the cribriform plate, and the frontal region without vessel damages. Under general anesthesia, the harpoon was pulled out in order to extract the shaft tip and the articulated wishbone. Osteo-meningeal defect of the ethmoid roof was closed using a middle turbinate flap. There were no neurologic deficit and no cerebro-spinal rhinorrhea at his 3-year follow-up visit. The trajectory of the shaft is different between attempted suicide and accident. Cranial CT scan is helpful to show the trajectory of the shaft. Angiogram can be helpful to see the relations between the tip shaft and the vessels. The knowledge of the shaft tip and the imagery findings are important to decide the best surgical approach.

[Isolated factor X deficiency in chronic myelomonocytic leukemia: Report of one case]. / Déficit adquirido de factor X en leucemia mielomonocítica crónica: reporte de un caso.

Bleeding disorders are commonly associated with hemato-oncologic diseases. We report a 68 years old male with a chronic myelomonocytic leukemia derived from a long lasting mielodysplastic syndrome that did not respond to treatment with Azacitidine. The patient was hospitalized due to tonic clonic seizures. A CAT scan showed a hematoma in the frontal lobe. A new assessment of hemostasis revealed an isolated deficiency of Factor X. We speculate that this deficit could be secondary to consumption due to the chronic Myelomonocytic Leukemia.

[Concomitant anosmia and ageusia: a case report]. / Anosmie et agueusie: è propos d'un cas.

Olfactory loss due to head trauma is a frequent finding. It is attributed to the tearing or severing of the olfactory fibers at the cribriform plate. In contrast, posttraumatic gustatory loss is observed and reported rarely and the underlying mechanism is less understood. Here we present a case of a concomitant post-traumatic anosmia and ageusia. Imaging showed a considerable frontobasal brain damage and it is speculated that the gustatory impairment is due to a central injury of the secondary taste cortex. Based on this observation, we believe that this clinical presentation might be much more frequent than previously reported.

Simple tone discriminations are disrupted following experimental frontal traumatic brain injury in rats.

PRIMARY OBJECTIVE: To assess cognitive deficits in a rat model of brain injury. RESEARCH DESIGN: Cognitive deficits are some of the most pervasive and enduring symptoms of frontal traumatic brain injury (TBI) in human patients. In animal models, the assessment of cognitive deficits from TBI has primarily been limited to tests of spatial learning. Recently, simple discrimination performance has been shown to be sensitive to frontal brain damage. The current study provides a detailed characterization of deficits in a two-choice tone discrimination following a bilateral frontal controlled cortical impact injury. METHODS AND PROCEDURES: Rats were trained on a two-tone discrimination task in a standard operant chamber, then either a frontal brain injury was delivered or sham procedures performed. Following recovery, they were re-tested on the discrimination task and then tested on a reversal of the discrimination. MAIN OUTCOMES AND RESULTS: Frontal injury caused substantial deficits in responding and discrimination accuracy as well as an increase in side bias. CONCLUSIONS: Based on the outcomes seen in this study, discrimination and other operant tasks may provide a sensitive tool to assess the effect of therapeutic agents on cognitive deficits in animal models, which could lead to improved characterization of deficits and yield an improved assessment tool to aid in drug discovery.

Fatal gunshot wound to the head with lack of immediate incapacitation.

Investigation of deaths caused by penetrating gunshot wounds to the head often raises the possibility of foul play. The forensic pathologist may be asked if the victim was able to perform certain acts after the gunshot, and how quickly this person might have become incapacitated. The possibility of a suicidal act can depend on these answers. We report the case of a 45-year-old woman whose body was found with a right temporal entrance wound. A shotgun was found 60 ft from the body location. The question of knowing if this woman had been able to shoot herself in the head and then walk a distance of 60 ft before dying was essential for the investigation, as suicide was the first hypothesis. The autopsy and a careful neuropathology investigation allowed to answer this question. In the literature, multiple publications report cases of victims who were able to act following penetrating ballistic head injury.

Intracranial meningioma at the site of a previous cranial penetrating trauma due to shrapnel.

Meningiomas are common and mostly benign intracranial tumors, which originate from arachnoid cells of the meninges, and account for approximately 25% of all primary intracranial tumors. Many external etiological factors have been described as etiology of meningioma in the literature, one of which is head trauma. However, trauma as a cause of meningioma remains a controversial subject. Here, a case of a patient with posttraumatic meningioma, who was wounded 25 years before, is presented. The assessment of the clinical characteristics of the patient and those reported in the literature seem to confirm that, in some cases, head trauma may be a factor contributing to the development of meningioma.