Focused ultrasound-assisted delivery of immunomodulating agents in brain cancer.

Focused ultrasound (FUS) combined with intravascularly circulating microbubbles can transiently increase the permeability of the blood-brain barrier (BBB) to enable targeted therapeutic delivery to the brain, the clinical testing of which is currently underway in both adult and pediatric patients. Aside from traditional cancer drugs, this technique is being extended to promote the delivery of immunomodulating therapeutics to the brain, including antibodies, immune cells, and cytokines. In this manner, FUS approaches are being explored as a tool to improve and amplify the effectiveness of immunotherapy for both primary and metastatic brain cancer, a particularly challenging solid tumor to treat. Here, we present an overview of the latest groundbreaking research in FUS-assisted delivery of immunomodulating agents to the brain in pre-clinical models of brain cancer, and place it within the context of the current immunotherapy approaches. We follow this up with a discussion on new developments and emerging strategies for this rapidly evolving approach.

Current and Emerging Systems for Focused Ultrasound-Mediated Blood-Brain Barrier Opening.

With an ever-growing list of neurological applications of focused ultrasound (FUS), there has been a consequent increase in the variety of systems for delivering ultrasound energy to the brain. Specifically, recent successful pilot clinical trials of blood-brain barrier (BBB) opening with FUS have generated substantial interest in the future applications of this relatively novel therapy, with divergent, purpose-built technologies emerging. With many of these technologies at various stages of pre-clinical and clinical investigation, this article seeks to provide an overview and analysis of the numerous medical devices in active use and under development for FUS-mediated BBB opening.

Third Nerve Palsy Due to Intracranial Aneurysms and Recovery after Endovascular Coiling.

INTRODUCTION: The modality of treatment of third nerve palsy (TNP) associated with intracranial aneurysms remains controversial. While treatment varies with the location of the aneurysm, microsurgical clipping of PComm aneurysms has generally been the traditional choice, with endovascular coiling emerging as a reasonable alternative. METHODS: Patients with TNP due to an intracranial aneurysm who subsequently underwent treatment at a mid-sized Canadian neurosurgical center over a 15-year period (2003-2018) were examined. RESULTS: A total of 616 intracranial aneurysms in 538 patients were treated; the majority underwent endovascular coiling with only 24 patients treated with surgical clipping. Only 37 patients (6.9%) presented with either a partial or complete TNP and underwent endovascular embolization; of these, 17 presented with a SAH secondary to intracranial aneurysm rupture. Aneurysms associated with TNP included PComm (64.9%), terminal ICA (29.7%), proximal MCA (2.7%), and basilar tip (2.7%) aneurysms. In general, smaller aneurysms and earlier treatment were provided for patients for ruptured aneurysms with a shorter mean interval to TNP recovery. In the endovascularly treated cohort initially presenting with TNP, seven presented with a complete TNP and the remaining were partial TNPs. TNP resolved completely in 20 patients (55.1%) and partially in 10 patients (27.0%). Neither time to coiling nor SAH at presentation were significantly associated with the recovery status of TNP. CONCLUSION: Endovascular coil embolization is a viable treatment modality for patients presenting with an associated cranial nerve palsy.

Paralysie du troisième nerf en raison d'un anévrisme intracrânien et rétablissement après la pose d'une bobine endovasculaire. INTRODUCTION: Les modalités de traitement de la paralysie du troisième nerf (PTN) associée aux anévrismes intracrâniens demeurent controversées. Bien que les traitements varient selon l'emplacement de l'anévrisme, le clippage (ou clipping) microchirurgical des anévrismes affectant les artères communicantes postérieures (ACP) est généralement apparu comme le choix le plus courant, la pose d'une bobine endovasculaire (endovascular coiling) ayant aussi émergé comme une option raisonnable. MÉTHODES: Nous nous sommes penchés sur les cas de patients atteints de PTN en raison d'un anévrisme intracrânien qui ont ensuite bénéficié d'un traitement dans un centre neurochirurgical canadien de taille moyenne, et ce, sur une période de 15 ans (2003 à 2018). RÉSULTATS: Au total, 616 anévrismes intracrâniens ayant affecté 538 patients ont été traités. La majorité d'entre eux ont bénéficié de la pose d'une bobine endovasculaire alors que seulement 24 patients ont été traités par clippage microchirurgical. Fait à noter, seuls 37 patients (6,9 %) ont donné à voir une PTN partielle ou totale et ont bénéficié d'une embolisation endovasculaire. De ce nombre, 17 ont donné à voir une hémorragie sous-arachnoïdienne (HSA) consécutive à une rupture d'anévrisme intracrânien. Les anévrismes associés à la PTN ont inclus les ACP (64,9 %), l'artère carotide interne terminale (29,7%), l'artère cérébrale moyenne proximale (2,7 %) et la pointe (tip) de l'artère basilaire (2,7 %). En général, un traitement plus précoce a été proposé aux patients victimes de plus petites ruptures d'anévrisme associées à des délais moyens de rétablissement plus courts à la suite d'une PTN. Dans la cohorte de patients ayant donné à voir des signes de PTN et ayant bénéficié d'un traitement endovasculaire, 7 d'entre eux étaient atteints d'une PTN complète alors que les autres étaient atteints d'une PTN partielle. Les signes de PTN ont fini par disparaître complètement chez 20 patients (55,1 %) et partiellement chez 10 autres (27,0 %). Ni les délais dans la pose d'une bobine endovasculaire ni des signes de HSA au moment de consulter n'ont été notablement associés au processus de rétablissement à la suite d'une PTN. CONCLUSION: En somme, il ressort que l'embolisation endovasculaire au moyen de bobines est une modalité de traitement viable pour les patients présentant une paralysie des nerfs crâniens.

Sex-specific effects of the histone variant H2A.Z on fear memory, stress-enhanced fear learning and hypersensitivity to pain.

Emerging evidence suggests that histone variants are novel epigenetic regulators of memory, whereby histone H2A.Z suppresses fear memory. However, it is not clear if altered fear memory can also modify risk for PTSD, and whether these effects differ in males and females. Using conditional-inducible H2A.Z knockout (cKO) mice, we showed that H2A.Z binding is higher in females and that H2A.Z cKO enhanced fear memory only in males. However, H2A.Z cKO improved memory on the non-aversive object-in-place task in both sexes, suggesting that H2A.Z suppresses non-stressful memory irrespective of sex. Given that risk for fear-related disorders, such as PTSD, is biased toward females, we examined whether H2A.Z cKO also has sex-specific effects on fear sensitization in the stress-enhanced fear learning (SEFL) model of PTSD, as well as associated changes in pain sensitivity. We found that H2A.Z cKO reduced stress-induced sensitization of fear learning and pain responses preferentially in female mice, indicating that the effects of H2A.Z depend on sex and the type of task, and are influenced by history of stress. These data suggest that H2A.Z may be a sex-specific epigenetic risk factor for PTSD susceptibility, with implications for developing sex-specific therapeutic interventions.

Immunogenicity of a recombinant, yeast-derived, anti-hepatitis-B vaccine after alternative dosage and schedule vaccination in Pakistani children.

A controlled, randomized trial was conducted in urban areas of Karachi and Lahore with the aim to look for ways to improve the cost-effectiveness of hepatitis B vaccination. Children under 15 years old (including neonates) were selected and screened for immunization by three regimens according to the frequency and doses of the recombinant vaccine used (Heberbiovac HB, Heber Biotec, Havana). Group A received 10 microg at 0, 1 months; group B (control) received 10 microg at 0, 1 and 2 months (standard regime), and group C received 5 microg at 0, 1 and 2 months. Antibody levels were titrated 2 months after the last dose. Cut-off for seroprotection and hyperresponse were taken as 10 and 100 IU/L, respectively. Nine hundred and ninety children were included and evaluated after discarding those positive for serological hepatitis virus infection markers. Seroprotection rates were 100, 99.7 and 99.7%, and hyperresponse was achieved by 92.7, 99.4, and 97% of the vaccinees in groups A, B, and C, respectively. The same good result was obtained in extreme ages subgroups (< or =1 year and > or =10 years old). The 1-year follow up of the children from Karachi showed good persistence of seroprotection (98, 100, and 99.4%) and hyperresponse (79.7, 96.7, and 87.4%). It is concluded that it is feasible to improve the cost-benefit ratio and compliance of hepatitis B vaccination by means of a two-shots or reduced dose schedule of the vaccine employed in the trial.