Perspectives on the Mechanism of Action of Electroconvulsive Therapy: Anticonvulsant, Peptidergic, c-fos Proto-oncogene Effects

Although the mechanism of action of electroconvulsive therapy (ECT) in affective illness has remained elusive, it is hoped that the consideration of mechanisms underlying the anticonvulsant efficacy of ECT will provide new insights into its biochemical and neuroanatomical substrates. In the amygdala-kindling model, electroconvulsive seizures (ECS) inhibit both the development and completed phases of kindled seizure evolution, and therefore, ECS is a more potent anticonvulsant modality than carbamazepine, which inhibits only completed kindled seizures. Carbamazepine is increasingly recognized for its acute and prophylactic efficacy in bipolar affective illness. Thus, comparing and contrasting effects of ECS and carbamazepine may provide insights into overlapping mechanisms of anticonvulsant and psychotropic action. Anticonvulsant effects of ECS have been most closely linked to endogenous opiate substances, perhaps acting on delta-opiate receptors, but a wide variety of other neurotransmitter and peptidergic effects are also potential candidates. Electroconvulsive seizures in mice activate the proto-oncogene c-fos in many discrete areas of brain, including a variety of limbic sites, the ventromedial nucleus of the hypothalamus, and the cerebellum. As such, c-fos induction may provide both an anatomical map of areas potentially activated by ECS and a potential mechanism for initiating a sequence of events that may be important to the mechanism of action of ECT. Although the anticonvulsant effects of ECT may ultimately prove to be separable from those mediating its therapeutic effects in affective illness, seizures and anticonvulsant effects provide easily measurable endpoints for preclinical and clinical studies. Given this clarity of effect, potential anticonvulsant mechanisms can rapidly be identified, enabling direct testing of whether or not these same mechanisms are also critical to the therapeutic effects of ECT in affective illness.     

Genetic analysis and attribution of microbial forensics evidence

Because of the availability of pathogenic microorganisms and the relatively low cost of preparing and disseminating bioweapons, there is a continuing threat of biocrime and bioterrorism. Thus, enhanced capabilities are needed that enable the full and robust forensic exploitation and interpretation of microbial evidence from acts of bioterrorism or biocrimes. To respond to the need, greater resources and efforts are being applied to the burgeoning field of microbial forensics. Microbial forensics focuses on the characterization, analysis and interpretation of evidence for attributional purposes from a bioterrorism act, biocrime, hoax or inadvertent agent release. To enhance attribution capabilities, a major component of microbial forensics is the analysis of nucleic acids to associate or eliminate putative samples. The degree that attribution can be addressed depends on the context of the case, the available knowledge of the genetics, phylogeny, and ecology of the target microorganism, and technologies applied. The types of genetic markers and features that can impact statistical inferences of microbial forensic evidence include: single nucleotide polymorphisms, repetitive sequences, insertions and deletions, mobile elements, pathogenicity islands, virulence and resistance genes, house keeping genes, structural genes, whole genome sequences, asexual and sexual reproduction, horizontal gene transfer, conjugation, transduction, lysogeny, gene conversion, recombination, gene duplication, rearrangements, and mutational hotspots. Nucleic acid based typing technologies include: PCR, real-time PCR, MLST, MLVA, whole genome sequencing, and microarrays.     

Developmental coordination disorder and aerobic fitness: is it all in their heads or is measurement still the problem?

Developmental coordination disorder (DCD) is characterized by motor inproficiency, resulting in significant impairments in social and/or academic functioning. About 5-9% of all school-age children are affected. Previous research has shown that children with DCD have lower aerobic fitness levels than children without the disorder, although the reasons for this have not been tested in the literature. A potential explanation may lie in perceived adequacy regarding performance in physical activity. Although negative perceptions of adequacy in children with DCD likely reflect an accurate appraisal of actual physical abilities, aerobic fitness tests typically require minimal coordination skills. Children who perceive themselves to be less adequate are unlikely to persist at a task and may give up sooner on these tests of endurance. Using a large community based sample of children ages 9 through 14 (n=586), we examine whether differences in aerobic fitness (assessed by performance on a 20-m shuttle run test) between children who meet the criteria for DCD (n=44) and those who do not (n=542) is due to differences in perceived adequacy toward physical activity. Our results show that one-third of the effect of DCD on VO(2) can be attributed to differences in perceived adequacy. These results suggest that at least part of the reason children perform less well on tests of aerobic endurance is because they do not believe themselves to be as adequate as other children at physically active pursuits. The implications of this for further research are discussed.     

Safety and immunogenicity of adjuvanted recombinant subunit herpes zoster vaccine in lung transplant recipients

Lung transplant recipients are at high risk for herpes zoster and preventive measures are a significant unmet need. We investigated the safety and immunogenicity of two doses of a recombinant zoster vaccine (RZV) in lung transplant recipients (≥50 years). We enrolled 50 patients of which 49 received at least one vaccine dose. Anti-glycoprotein E (gE) antibody levels (n = 43) increased significantly compared to baseline (median optical density [OD] 1.96; interquartile range [IQR]: 1.17–2.89) after the first (median OD 3.41, IQR 2.54–3.81, p < .0001) and second vaccine dose (median OD 3.63, IQR 3.39–3.86, p < .0001). gE-specific polyfunctional CD4+ T cell frequencies (n = 38) also increased from baseline (median 85 per 10⁶ CD4+ T cells; IQR: 46–180) to the first (median 128 per 10⁶ CD4+ T cells; IQR: 82–353; p = .023) and after the second dose (median 361 per 10⁶ CD4+ T cells; IQR: 146–848; p < .0001). Tenderness (83.0%; 95%CI: 69.2–92.4%) and redness (31.9%; 95%CI: 19.1–47.1%) at injection site were common. One rejection episode within 3 weeks of vaccination was observed. This is the first study demonstrating that RZV was safe and elicited significant humoral and cell-mediated immunity in lung transplant recipients. RZV is a new option for the prevention of shingles in this population.     

Piriformis pyomyositis mimicking epidural abscess in a parturient

A case is presented of a patient who developed fever, leukocytosis, severe back pain, local overlying spinal tenderness, and left leg weakness on the fifth day postpartum. The patient had epidural anaesthesia for ten hours duration, before and during a forceps delivery. Computerized axial tomography (CT) and magnetic resonance imaging (MRI) of the pelvis and lumbar spine revealed swelling of the left iliacus and piriformis muscles, but no epidural abscess. A diagnosis of isolated piriformis pyomyositis with secondary sciatic nerve irritation was made, and the patient was treated with intravenous antibiotics, non-steroidal anti-inflammatory agents, and morphine analgesia. She made a full, uneventful recovery within 50 days, and was discharged requiring no medications.     

Airway management in neuroanaesthesia

Purpose

Airway management in neurosurgical patients pre sents unique challenges to the anaesthetist. This review will consider specific approaches to numerous problems in airway management related to logistical, physiological and anatomi cal concerns. The goal is to provide a clinically oriented and practical discussion regarding issues of airway management in neurosurgical patients.

Source

The recent literature has been reviewed regarding airway management options and related perioperative complications in the neurosurgical population. This is interlaced with approaches to many of the problems and their solutions based on experience gained in a very busy university neurosurgical practice over the past decade.

Principal findings

Specific pathophysiological alterations in the neurosurgical patient influence the technique chosen for securing an airway. These relate to the presence of increased intracranial pressure, intracranial aneurysms or arteriovenous malformations. Other important disordes influencing airway management include severe coronary artery disease, acromegaly and congenital airway difficulties. Stereotactic neurosurgery and conscious sedation for various neurosurgical procedures also provide unique challenges. There are other considerations unique to the neurosurgical patient such as intra- and postoperative airway obstruction and the timing of postoperative extubation.

Conclusion

The demands for airway management in neu roanaesthesia require expertise in the various modes of secur ing the airway while considering the patient’s physiological requirements as well as the unique surgical demands.     

Treatment of human tumor xenografts with monoclonal antibody 806 in combination with a prototypical epidermal growth factor receptor-specific antibody generates enhanced antitumor activity.

Monoclonal antibody (mAb) 806 is a novel epidermal growth factor receptor (EGFR) antibody with significant antitumor activity that recognizes a mutant EGFR commonly expressed in glioma known as delta2-7 EGFR (de2-7 EGFR or EGFRvIII) and a subset of the wild-type (wt) EGFR found in cells that overexpress the receptor. We have used two human xenograft mouse models to examine the efficacy of mAb 806 in combination with mAb 528, a prototypical anti-EGFR antibody with similar specificity to cetuximab. Treatment of nude mice, bearing s.c. or i.c. tumor human xenografts expressing the wt or de2-7 EGFR, with mAbs 806 and 528 in combination resulted in additive and in some cases synergistic, antitumor activity. Interestingly, mAb 528 was also effective against xenografts expressing the ligand independent de2-7 EGFR when used as a single agent, showing that its antitumor activity is not merely mediated through inhibition of ligand binding. When used as single agents, neither mAbs 806 or 528 induced down-regulation of the de2-7 EGFR either in vitro or in vivo. In contrast, the combination of antibodies produced a rapid and dramatic decrease in the total cell surface de2-7 EGFR both in vitro and in xenografts. Consistent with this decrease in total cell surface de2-7 EGFR, we observed up-regulation of the cell cycle inhibitor p27(KIP1) and a decrease in tumor cell proliferation as measured by Ki-67 immunostaining when the antibodies were used in combination in vivo. Thus, mAb 806 can synergize with other EGFR-specific antibodies thereby providing a rationale for its translation into the clinic.