Laminectomy for acute transverse sacral fractures with compression of the cauda equina: A neurosurgical perspective.

Introduction: Optimal management of transverse sacral fractures (TSF) remains inconclusive. These injuries may present with neurological deficits including cauda equina syndrome. We present our series of laminectomy for acute TSF with cauda equina compression. Methods: This was a retrospective chart review of all patients that underwent sacral laminectomy for treatment of cauda equina compression in acute TSF at our institution between 2007 through 2023. Results: A total of 9 patients (5 male and 4 female) underwent sacral laminectomy to decompress the cauda equina in the setting of acute high impact trauma. Surgeries were done early within a mean time of 5.9 days. All but one patient had symptomatic cauda equina syndrome. In one instance surgery was applied due to significant canal stenosis present on imaging in a patient with diminished mental status not allowing proper neurological examination. Torn sacral nerve roots were repaired directly when possible. All patients regained their neurological function related to the sacral cauda equina on follow up. The rate of surgical site infection (SSI) was 33%. Conclusion: Acute early sacral laminectomy and nerve root repair as needed was effective in recovering bowel and bladder function in patients after high impact trauma and TSF with cauda equina compression. A high SSI rate may be reduced by delaying surgery past 1 week from trauma, but little data exists at this time for clear recommendations.

A comprehensive approach to identifying repurposed drugs to treat SCN8A epilepsy.

OBJECTIVE: Many previous studies of drug repurposing have relied on literature review followed by evaluation of a limited number of candidate compounds. Here, we demonstrate the feasibility of a more comprehensive approach using high-throughput screening to identify inhibitors of a gain-of-function mutation in the SCN8A gene associated with severe pediatric epilepsy. METHODS: We developed cellular models expressing wild-type or an R1872Q mutation in the Nav 1.6 sodium channel encoded by SCN8A. Voltage clamp experiments in HEK-293 cells expressing the SCN8A R1872Q mutation demonstrated a leftward shift in sodium channel activation as well as delayed inactivation; both changes are consistent with a gain-of-function mutation. We next developed a fluorescence-based, sodium flux assay and used it to assess an extensive library of approved drugs, including a panel of antiepileptic drugs, for inhibitory activity in the mutated cell line. Lead candidates were evaluated in follow-on studies to generate concentration-response curves for inhibiting sodium influx. Select compounds of clinical interest were evaluated by electrophysiology to further characterize drug effects on wild-type and mutant sodium channel functions. RESULTS: The screen identified 90 drugs that significantly inhibited sodium influx in the R1872Q cell line. Four drugs of potential clinical interest-amitriptyline, carvedilol, nilvadipine, and carbamazepine-were further investigated and demonstrated concentration-dependent inhibition of sodium channel currents. SIGNIFICANCE: A comprehensive drug repurposing screen identified potential new candidates for the treatment of epilepsy caused by the R1872Q mutation in the SCN8A gene.

Parthenolide prodrug LC-1 slows growth of intracranial glioma.

LC-1 (also known as DMAPT or dimethylamino-parthenolide), a prodrug of parthenolide, was tested for anti-proliferative activity against glioma. LC-1 was found to have low micromolar cytotoxic activity against three glioma cell lines and was also found to be brain penetrant in healthy mice (2.1-3.0 brain-to-plasma ratio). In a syngeneic GL261 murine glioma model, LC-1 slowed tumor growth kinetics and extended the survival time of tumor-bearing mice in comparison to the vehicle control. Consequently, LC-1 represents a promising lead compound for further development as a glioma therapy.

Decreased affinity for efflux transporters increases brain penetrance and molecular targeting of a PI3K/mTOR inhibitor in a mouse model of glioblastoma.

BACKGROUND: Targeting drug delivery to invasive glioma cells is a particularly difficult challenge because these cells lie behind an intact blood-brain barrier (BBB) that can be observed using multimodality imaging. BBB-associated efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) influence drug distribution to these cells and may negatively impact efficacy. To test the hypothesis that efflux transporters influence brain pharmacokinetics/pharmacodynamics of molecularly targeted agents in glioma treatment, we assessed region-specific penetrance and molecular-targeting capacity for a PI3K/mTOR kinase inhibitor that has high substrate affinity for efflux transporters (GDC-0980) and an analog (GNE-317) that was purposely designed to have reduced efflux. METHODS: Brain tumor penetrance of GDC-0980 and GNE-317 was compared between FVB/n wild-type mice and Mdr1a/b(-/-)Bcrp(-/-) triple-knockout mice lacking P-gp and BCRP. C57B6/J mice bearing intracranial GL261 tumors were treated with GDC-0980, GNE-317, or vehicle to assess the targeted pharmacokinetic/pharmacodynamic effects in a glioblastoma model. RESULTS: Animals treated with GNE-317 demonstrated 3-fold greater penetrance in tumor core, rim, and normal brain compared with animals dosed with GDC-0980. Increased brain penetrance correlated with decreased staining of activated p-Akt, p-S6, and p-4EBP1 effector proteins downstream of PI3K and mTOR. CONCLUSIONS: GDC-0980 is subject to active efflux by P-gp and BCRP at the BBB, while brain penetrance of GNE-317 is independent of efflux, which translates into enhanced inhibition of PI3K/mTOR signaling. These data show that BBB efflux by P-gp and BCRP is therefore an important determinant in both brain penetrance and molecular targeting efficacy in the treatment of invasive glioma cells.

[Pulmonary embolism in the context of severe envenomation by a Moroccan viper]. / Embolie pulmonaire dans les suites d'une envenimation grave par une vipère marocaine.

Heparin, which was widely used thirty years ago for the treatment of viper envenomations, is now contra-indicated during the acute phase, which is at risk for hemorrhage and death. We report a case of pulmonary embolism, a rare situation in the context of viper envenomation. By means of this case report, we want to discuss the pathophysiological links between envenomation and thromboembolic disease, and on the other hand, the potential heparin usefulness, not during the acute, hemorrhagic phase, but as a prophylactic treatment when hemorrhagic risk has been replaced by an inflammatory syndrome, with increased fibrinogen and platelets which are then prothrombotic factors.

[Ischaemic stroke secondary to viper envenomation in Morocco in the absence of adequate antivenom]. / Accident vasculaire cérébral ischémique à la suite d'une envenimation vipérine grave au Maroc, traitée par un antivenin inadapté

An ischaemic stroke is a rare complication of viper envenomation that is due to multifactorial pathophysiological mechanisms. The authors describe the case of a 55-year-old patient bitten by the viper Cerastes cerastes. The patient was admitted to the intensive care unit with multiple organ failure, disseminated intravascular coagulopathy, rhabdomyolysis, anuria and elevated troponin level. The persistent disturbance of consciousness has motivated a brain scan which has revealed a bifocal ischemic stroke. The complex venom of the species C. cerastes may induce hypotension, tissue necrosis, acute renal failure, bleeding disorders or DIC. With the cessation of a non-indicated heparintherapy and haemodialysis, the patient recovered in a few weeks despite the initial infusion of an unsuitable antivenom due to the late identification of the reptile. The preventive treatment of the complications of this envenomation is based on the infusion of the polyvalent antivenom Favirept(®).

[Acute respiratory distress syndrome caused by tropical eosinophilic lung disease: a case in Gabon]. / Syndrome de détresse respiratoire aiguë révélateur d'un poumon éosinophile tropical : une observation au Gabon.

The purpose of this report is to describe the case of a 28-year-old woman in whom acute respiratory distress syndrome (ARDS) following cholecystectomy led to the discovery of eosinophilic lung disease. Outcome was favorable after oxygenotherapy and medical treatment using ivermectin and corticosteroids. The case shows that hypereosinophilic syndrome can be the underlying cause of ARDS.

[Three case-reports of viperin envenoming in Morocco]. / A propos de trois observations d'envenimations vipérines graves au Maroc.

Snake bites are responsible for a high mortality rate in Africa. Problems for the early care of the victims are many. We published three observations of Moroccan typical viperin severe envenomings (rapidly extensive edema, necrosis, haemorrhagic shock) are presented. The overall mortality of those bites is 4%. In the Maghreb, viperin syndromes are the result of the lebetin viper (Vipera lebetina), the horned viper or sand viper (Cerastes cerastes), sometimes Bitis or Echis sp. Immunotherapy remains effective against haemorrhage, even when administered late, in severe disease (bleeding). Death remains inevitable if antivenin is not being administered or if it is at the stage of multiorgan failure. Heparin is contra-indicated in the acute context, but at distance from the bite, the persistence of inflammatory syndrome can cause phlebitis or pulmonary embolism. Fresh frozen plasma and corticosteroids are ineffective and unnecessary. Signs of gravity are rapidly extensive swelling and systemic manifestations, particularly bleeding. The severity of poisoning is related to the difficulties of access to health centers, the use of traditional medicine for more than half of the victims, the lack of training of caregivers, finally and most importantly, the lack of antivenomous serum,that is not within reach of prescribing at the appropriate places and times. Despite its cost and allergic risk (become rare with the current serums), immunotherapy which is the only weapon effective against the venom, should be part of emergency essential drugs.

[Does tropical environment influence morbidity and mortality?]. / Le contexte tropical influence t-il la morbidite et la mortalite?

Despite enormous progress in medical science, health care coverage in poor countries remains incomplete, uncertain and minimal. The probability of death is higher in Africa. Life expectancy is only from 50 to 55 on the African continent in comparison with over 70 years in North America and Europe. The African population is predominantly young but malnutrition, deficiencies, anemia, parasitism and genetic defects (drepanocytemia) are widespread. In general treatment of acute trauma and illness is straightforward and vital or functional prognosis is good provided that proper elementary care is administered rapidly. However due to difficult field conditions and limited medical facilities, care is often delayed. Most patients are admitted with advanced, complicated disease to facilities that are often poorly equipped, undersupplied and lacking in qualified personnel, basic medication and blood products. This combination of factors accounts in part for the fact that prognosis of the same disease is poorer in tropical areas than in other areas of the world. Rational use of human resources and better organization of international cooperation would allow short-term improvement in health care in tropical areas. It is only at this price that people in the Northern and Southern hemisphere in this time of globalization can have the same chance of survival for the same disease.