Recent Cases

Constitutional Law-First Amendment-School Authorities May Prohibit High School Student\u27s Distribution of Sex Questionnaire to Prevent Possible Psychological Harm to Other Students Robert Edward Banta Plaintiff, editor of a high school publication,\u27 brought suit in federal court seeking an order compelling defendant school officials to allow the student publication to distribute a sex questionnaire,to students in the high school and to publish the results. Plaintiff claimed that defendants had not shown that the planned distribution would disrupt school activities and that, therefore, defendants\u27prohibition of the questionnaire violated 42 U.S.C. § 19831 and the first and fourteenth amendments. Pointing to potential psychological harm to students, defendants argued that the state\u27s interest in protecting the students\u27 emotional well-being outweighed plaintiffs interest in distributing the questionnaire. The trial court held that defendants could prohibit distribution of the questionnaire to ninth-and tenth-grade students but not to eleventh- and twelfth-grade students. On appeal to the United States Court of Appeals for the Second Circuit, held, reversed in part\u27 and remanded with instructions to dismiss the complaint. If school officials reasonably believe that distribution on school grounds of a high school student\u27s questionnaire soliciting information about the sexual habits of his fellow students might cause psychological harm to other students, then prohibition of the questionnaire does not violate the right to freedom of expression of the student seeking to distribute the questionnaire. Trachtman v. Anker, 563 F.2d 512 (2d Cir. 1977). Corporations--Freeze-Out Mergers--The Delaware Supreme Court Requires Majority Shareholder Proof of a Valid Business Purpose As a Component of Entire Fairness in Freeze-Out Merger Challenges Oby T. Brewer, III Recent declines in stock market averages\u27 accompanied by costly disclosure requirements imposed under the federal securities laws have prompted many companies to reconsider their positions as publicly held corporations. In response to the resulting minimal benefits of public ownership, many controlling shareholders now seek to increase their control and participation in a corporation\u27s future profits by going private.\u27 One means of going private is the freeze-out merger, by which a parent company forces the liquidation of minority interests in a publicly held subsidiary through a merger of the subsidiary with the parent. By complying with applicable state merger statutes, the parent may eliminate the minority\u27s shares by tendering a cash-out price, which the minority either must accept or have appraised judicially. The merger statutes thus represent a legislative compromise between total majority control and the single vote veto available to the minority at common law. Criminal Procedure--Prosecutorial Immunity-Federal Prosecutor Is Not Absolutely Immune From Suit for Alleged Perjury Cornelia Anne Clark Plaintiffs\u27 brought a civil action in tort charging that defendant federal prosecutor\u27s alleged perjury at a hearing incident to a grand jury investigation of plaintiffs\u27 activities\u27 violated their constitutional rights. On motion to dismiss, defendant contended that he enjoyed absolute quasi-judicial immunity because he had been acting at the hearing in his official capacity as a special federal prosecutor. The district court\u27 denied the motion, holding that the doctrine of quasi-judicial immunity does not apply when the prosecutor is alleged to have committed perjury. On interlocutory appeal to the United States Court of Appeals for the District of Columbia Circuit, held, affirmed. Because a federal prosecutor\u27s perjury during a court hearing incident and prior to a grand jury investigation falls within his investigative duty rather than his advocatory duty,the prosecutor is entitled only to a qualified immunity.\u27 Briggs v.Goodwin, No. 75-1642 (D.C. Cir. Sept. 21, 1977). Securities Law--Rule 10b-5-Defense of In Pari Delicto Bars Private Damage Action Brought Against Tipper by Tippee Who Fails to Disclose Before Trading Terry Currie Tippees\u27 brought a private action for damages under section 10(b) of the Securities Exchange Act of 1934 and rule 10b-53 charging that defendant tippers disseminated false and misleading material inside information in advising plaintiffs of an imminent merger between two corporations that would result in appreciated stock values.\u27 In reliance on this information, plaintiffs purchased stock in one of the corporations and subsequently incurred substantial losses on the stock when the proposed merger did not occur. Defendants moved for summary judgment, claiming that the doctrine of in pari delicto barred plaintiffs\u27 recovery because plaintiffs also had violated rule 10b-5 by failing to make full disclosure of the inside information before trading on the open market.\u27 The district court granted the tippers\u27 motion for summary judgment. On appeal to the United States Court of Appeals for the Third Circuit, held, affirmed. When a tippee violates rule 10b-5 by failing to make full disclosure to the investing public of material inside information prior to trading on the open market, the defense of in pari delicto bars a rule 10b-5 private damage action by the tippee against the tipper. Torts--Negligence--Child Has Cause of Action for Preconception Medical Malpractice Douglas William Ey, Jr. Plaintiff, claiming that she suffered permanent physical injuries\u27 as a result of defendants\u27 conduct prior to her conception,sought to recover damages in a negligence action.2 In 1965 plaintiffs mother,who had Rh negative blood, was given two transfusions of incompatible Rh positive blood in defendant hospital where defendant physician was director of laboratories.\u27 Plaintiff\u27s mother did not discover that these transfusions had sensitized her blood until shortly before plaintiffs birth in 1973. Defendants moved to dis-miss for failure to state a cause of action, arguing that because plaintiff had not been conceived at the time of the alleged negligent conduct, defendants owed no duty of care to plaintiff. The trial court granted defendants\u27 motion, but the Illinois Appellate Court reversed and remanded the case for further proceedings. On appeal to the Supreme Court of Illinois, held, affirmed. A child injured by the negligent acts of a physician and a hospital committed against his mother prior to his conception has a cause of action based on negligence. Renslow v. Mennonite Hospital, 367 N.E.2d 1250 (Ill.1977)

Toward the Restoration of Hand Use to a Paralyzed Monkey: Brain-Controlled Functional Electrical Stimulation of Forearm Muscles

Loss of hand use is considered by many spinal cord injury survivors to be the most devastating consequence of their injury. Functional electrical stimulation (FES) of forearm and hand muscles has been used to provide basic, voluntary hand grasp to hundreds of human patients. Current approaches typically grade pre-programmed patterns of muscle activation using simple control signals, such as those derived from residual movement or muscle activity. However, the use of such fixed stimulation patterns limits hand function to the few tasks programmed into the controller. In contrast, we are developing a system that uses neural signals recorded from a multi-electrode array implanted in the motor cortex; this system has the potential to provide independent control of multiple muscles over a broad range of functional tasks. Two monkeys were able to use this cortically controlled FES system to control the contraction of four forearm muscles despite temporary limb paralysis. The amount of wrist force the monkeys were able to produce in a one-dimensional force tracking task was significantly increased. Furthermore, the monkeys were able to control the magnitude and time course of the force with sufficient accuracy to track visually displayed force targets at speeds reduced by only one-third to one-half of normal. Although these results were achieved by controlling only four muscles, there is no fundamental reason why the same methods could not be scaled up to control a larger number of muscles. We believe these results provide an important proof of concept that brain-controlled FES prostheses could ultimately be of great benefit to paralyzed patients with injuries in the mid-cervical spinal cord

Subregional origins of emerging SARS-CoV-2 variants during the second pandemic wave in Côte d’Ivoire

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with increased transmissibility, virulence and immune escape abilities have heavily altered the COVID-19 pandemic’s course. Deciphering local and global transmission patterns of those variants is thus key in building a profound understanding of the virus’ spread around the globe. In the present study, we investigate SARS-CoV-2 variant epidemiology in Côte d’Ivoire, Western sub-Saharan Africa. We therefore generated 234 full SARS-CoV-2 genomes stemming from Central and Northern Côte d’Ivoire. Covering the first and second pandemic wave the country had been facing, we identified 20 viral lineages and showed that in Côte d’Ivoire the second pandemic wave in 2021 was driven by the spread of the Alpha (B.1.1.7) and Eta (B.1.525) variant. Our analyses are consistent with a limited number of international introductions of Alpha and Eta into Côte d’Ivoire, and those introduction events mostly stemmed from within the West African subregion. This suggests that subregional travel to Côte d’Ivoire had more impact on local pandemic waves than direct intercontinental travel.Peer Reviewe

The role of inflammation in epilepsy.

Epilepsy is the third most common chronic brain disorder, and is characterized by an enduring predisposition to generate seizures. Despite progress in pharmacological and surgical treatments of epilepsy, relatively little is known about the processes leading to the generation of individual seizures, and about the mechanisms whereby a healthy brain is rendered epileptic. These gaps in our knowledge hamper the development of better preventive treatments and cures for the approximately 30% of epilepsy cases that prove resistant to current therapies. Here, we focus on the rapidly growing body of evidence that supports the involvement of inflammatory mediators-released by brain cells and peripheral immune cells-in both the origin of individual seizures and the epileptogenic process. We first describe aspects of brain inflammation and immunity, before exploring the evidence from clinical and experimental studies for a relationship between inflammation and epilepsy. Subsequently, we discuss how seizures cause inflammation, and whether such inflammation, in turn, influences the occurrence and severity of seizures, and seizure-related neuronal death. Further insight into the complex role of inflammation in the generation and exacerbation of epilepsy should yield new molecular targets for the design of antiepileptic drugs, which might not only inhibit the symptoms of this disorder, but also prevent or abrogate disease pathogenesis

Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study

BACKGROUND: Most neonatal and infantile-onset epilepsies have presumed genetic aetiologies, and early genetic diagnoses have the potential to inform clinical management and improve outcomes. We therefore aimed to determine the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in this population. METHODS: We conducted an international, multicentre, cohort study (Gene-STEPS), which is a pilot study of the International Precision Child Health Partnership (IPCHiP). IPCHiP is a consortium of four paediatric centres with tertiary-level subspecialty services in Australia, Canada, the UK, and the USA. We recruited infants with new-onset epilepsy or complex febrile seizures from IPCHiP centres, who were younger than 12 months at seizure onset. We excluded infants with simple febrile seizures, acute provoked seizures, known acquired cause, or known genetic cause. Blood samples were collected from probands and available biological parents. Clinical data were collected from medical records, treating clinicians, and parents. Trio genome sequencing was done when both parents were available, and duo or singleton genome sequencing was done when one or neither parent was available. Site-specific protocols were used for DNA extraction and library preparation. Rapid genome sequencing and analysis was done at clinically accredited laboratories, and results were returned to families. We analysed summary statistics for cohort demographic and clinical characteristics and the timing, diagnostic yield, and clinical impact of rapid genome sequencing. FINDINGS: Between Sept 1, 2021, and Aug 31, 2022, we enrolled 100 infants with new-onset epilepsy, of whom 41 (41%) were girls and 59 (59%) were boys. Median age of seizure onset was 128 days (IQR 46-192). For 43 (43% [binomial distribution 95% CI 33-53]) of 100 infants, we identified genetic diagnoses, with a median time from seizure onset to rapid genome sequencing result of 37 days (IQR 25-59). Genetic diagnosis was associated with neonatal seizure onset versus infantile seizure onset (14 [74%] of 19 vs 29 [36%] of 81; p=0·0027), referral setting (12 [71%] of 17 for intensive care, 19 [44%] of 43 non-intensive care inpatient, and 12 [28%] of 40 outpatient; p=0·0178), and epilepsy syndrome (13 [87%] of 15 for self-limited epilepsies, 18 [35%] of 51 for developmental and epileptic encephalopathies, 12 [35%] of 34 for other syndromes; p=0·001). Rapid genome sequencing revealed genetic heterogeneity, with 34 unique genes or genomic regions implicated. Genetic diagnoses had immediate clinical utility, informing treatment (24 [56%] of 43), additional evaluation (28 [65%]), prognosis (37 [86%]), and recurrence risk counselling (all cases). INTERPRETATION: Our findings support the feasibility of implementation of rapid genome sequencing in the clinical care of infants with new-onset epilepsy. Longitudinal follow-up is needed to further assess the role of rapid genetic diagnosis in improving clinical, quality-of-life, and economic outcomes. FUNDING: American Academy of Pediatrics, Boston Children's Hospital Children's Rare Disease Cohorts Initiative, Canadian Institutes of Health Research, Epilepsy Canada, Feiga Bresver Academic Foundation, Great Ormond Street Hospital Charity, Medical Research Council, Murdoch Children's Research Institute, National Institute of Child Health and Human Development, National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre, One8 Foundation, Ontario Brain Institute, Robinson Family Initiative for Transformational Research, The Royal Children's Hospital Foundation, University of Toronto McLaughlin Centre

Efficacy of Anti-Inflammatory Therapy in a Model of Acute Seizures and in a Population of Pediatric Drug Resistant Epileptics

Targeting pro-inflammatory events to reduce seizures is gaining momentum. Experimentally, antagonism of inflammatory processes and of blood-brain barrier (BBB) damage has been demonstrated to be beneficial in reducing status epilepticus (SE). Clinically, a role of inflammation in the pathophysiology of drug resistant epilepsies is suspected. However, the use anti-inflammatory drug such as glucocorticosteroids (GCs) is limited to selected pediatric epileptic syndromes and spasms. Lack of animal data may be one of the reasons for the limited use of GCs in epilepsy. We evaluated the effect of the CG dexamethasone in reducing the onset and the severity of pilocarpine SE in rats. We assessed BBB integrity by measuring serum S100β and Evans Blue brain extravasation. Electrophysiological monitoring and hematologic measurements (WBCs and IL-1β) were performed. We reviewed the effect of add on dexamethasone treatment on a population of pediatric patients affected by drug resistant epilepsy. We excluded subjects affected by West, Landau-Kleffner or Lennox-Gastaut syndromes and Rasmussen encephalitis, known to respond to GCs or adrenocorticotropic hormone (ACTH). The effect of two additional GCs, methylprednisolone and hydrocortisone, was also reviewed in this population. When dexamethasone treatment preceded exposure to the convulsive agent pilocarpine, the number of rats developing status epilepticus (SE) was reduced. When SE developed, the time-to-onset was significantly delayed compared to pilocarpine alone and mortality associated with pilocarpine-SE was abolished. Dexamethasone significantly protected the BBB from damage. The clinical study included pediatric drug resistant epileptic subjects receiving add on GC treatments. Decreased seizure frequency (≥50%) or interruption of status epilepticus was observed in the majority of the subjects, regardless of the underlying pathology. Our experimental results point to a seizure-reducing effect of dexamethasone. The mechanism encompasses improvement of BBB integrity. Our results also suggest that add on GCs could be of efficacy in controlling pediatric drug resistant seizures

A hematopoietic contribution to microhemorrhage formation during antiviral CD8 T cell-initiated blood-brain barrier disruption

<p>Abstract</p> <p>Background</p> <p>The extent to which susceptibility to brain hemorrhage is derived from blood-derived factors or stromal tissue remains largely unknown. We have developed an inducible model of CD8 T cell-initiated blood-brain barrier (BBB) disruption using a variation of the Theiler's murine encephalomyelitis virus (TMEV) model of multiple sclerosis. This peptide-induced fatal syndrome (PIFS) model results in severe central nervous system (CNS) vascular permeability and death in the C57BL/6 mouse strain, but not in the 129 SvIm mouse strain, despite the two strains' having indistinguishable CD8 T-cell responses. Therefore, we hypothesize that hematopoietic factors contribute to susceptibility to brain hemorrhage, CNS vascular permeability and death following induction of PIFS.</p> <p>Methods</p> <p>PIFS was induced by intravenous injection of VP2_121-130peptide at 7 days post-TMEV infection. We then investigated brain inflammation, astrocyte activation, vascular permeability, functional deficit and microhemorrhage formation using T2*-weighted magnetic resonance imaging (MRI) in C57BL/6 and 129 SvIm mice. To investigate the contribution of hematopoietic cells in this model, hemorrhage-resistant 129 SvIm mice were reconstituted with C57BL/6 or autologous 129 SvIm bone marrow. Gadolinium-enhanced, T1-weighted MRI was used to visualize the extent of CNS vascular permeability after bone marrow transfer.</p> <p>Results</p> <p>C57BL/6 and 129 SvIm mice had similar inflammation in the CNS during acute infection. After administration of VP2_121-130peptide, however, C57BL/6 mice had increased astrocyte activation, CNS vascular permeability, microhemorrhage formation and functional deficits compared to 129 SvIm mice. The 129 SvIm mice reconstituted with C57BL/6 but not autologous bone marrow had increased microhemorrhage formation as measured by T2*-weighted MRI, exhibited a profound increase in CNS vascular permeability as measured by three-dimensional volumetric analysis of gadolinium-enhanced, T1-weighted MRI, and became moribund in this model system.</p> <p>Conclusion</p> <p>C57BL/6 mice are highly susceptible to microhemorrhage formation, severe CNS vascular permeability and morbidity compared to the 129 SvIm mouse. This susceptibility is transferable with the bone marrow compartment, demonstrating that hematopoietic factors are responsible for the onset of brain microhemorrhage and vascular permeability in immune-mediated fatal BBB disruption.</p

Interictal Functional Connectivity of Human Epileptic Networks Assessed by Intracerebral EEG and BOLD Signal Fluctuations

In this study, we aimed to demonstrate whether spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal derived from resting state functional magnetic resonance imaging (fMRI) reflect spontaneous neuronal activity in pathological brain regions as well as in regions spared by epileptiform discharges. This is a crucial issue as coherent fluctuations of fMRI signals between remote brain areas are now widely used to define functional connectivity in physiology and in pathophysiology. We quantified functional connectivity using non-linear measures of cross-correlation between signals obtained from intracerebral EEG (iEEG) and resting-state functional MRI (fMRI) in 5 patients suffering from intractable temporal lobe epilepsy (TLE). Functional connectivity was quantified with both modalities in areas exhibiting different electrophysiological states (epileptic and non affected regions) during the interictal period. Functional connectivity as measured from the iEEG signal was higher in regions affected by electrical epileptiform abnormalities relative to non-affected areas, whereas an opposite pattern was found for functional connectivity measured from the BOLD signal. Significant negative correlations were found between the functional connectivities of iEEG and BOLD signal when considering all pairs of signals (theta, alpha, beta and broadband) and when considering pairs of signals in regions spared by epileptiform discharges (in broadband signal). This suggests differential effects of epileptic phenomena on electrophysiological and hemodynamic signals and/or an alteration of the neurovascular coupling secondary to pathological plasticity in TLE even in regions spared by epileptiform discharges. In addition, indices of directionality calculated from both modalities were consistent showing that the epileptogenic regions exert a significant influence onto the non epileptic areas during the interictal period. This study shows that functional connectivity measured by iEEG and BOLD signals give complementary but sometimes inconsistent information in TLE