Anti-AMPA Receptor Autoantibodies Reduce Excitatory Currents in Rat Hippocampal Neurons.

The GluR3 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) has been identified as a target for autoantibodies (Aabs) in autoimmune encephalopathy and other diseases. Recent studies have proposed mechanisms by which these Aabs act, but their exact role in neuronal excitability is yet to be established. Patient Aabs have been shown to bind to specific regions within the GluR3 subunit. GLUR3B peptides were designed based on described (ELISA) immunogenic epitopes for Aabs and an immunisation strategy was used to generate novel anti-AMPAR Aabs. Target-specific binding and specificity of affinity-purified anti-AMPAR Aabs was confirmed using enzyme-linked immunosorbent assay, immunocytochemistry and Western blot. Functional anti-AMPAR Aab effects were determined on excitatory postsynaptic currents (EPSCs) from primary hippocampal neurons using whole-cell patch-clamp electrophysiology. Acute (10 or 30 min) or longer-term (24 h) application of anti-AMPAR Aabs caused a significant reduction in the mean frequency of spontaneous and miniature EPSCs in hippocampal neurons. Our data demonstrate that anti-AMPAR Aabs targeting peptides linked to auto-immune diseases mediate inhibitory effects on neuronal excitability at the synaptic level, such effects may lead to disruption of the excitatory/inhibitory balance at a network level.

CD1a promotes systemic manifestations of skin inflammation.

Inflammatory skin conditions are increasingly recognised as being associated with systemic inflammation. The mechanisms connecting the cutaneous and systemic disease are not well understood. CD1a is a virtually monomorphic major histocompatibility complex (MHC) class I-like molecule, highly expressed by skin and mucosal Langerhans cells, and presents lipid antigens to T-cells. Here we show an important role for CD1a in linking cutaneous and systemic inflammation in two experimental disease models. In human CD1a transgenic mice, the toll-like receptor (TLR)7 agonist imiquimod induces more pronounced splenomegaly, expansion of the peripheral blood and spleen T cell compartments, and enhanced neutrophil and eosinophil responses compared to the wild-type, accompanied by elevated skin and plasma cytokine levels, including IL-23, IL-1α, IL-1ß, MCP-1 and IL-17A. Similar systemic escalation is shown in MC903-induced skin inflammation. The exacerbated inflammation could be counter-acted by CD1a-blocking antibodies, developed and screened in our laboratories. The beneficial effect is epitope dependent, and we further characterise the five best-performing antibodies for their capacity to modulate CD1a-expressing cells and ameliorate CD1a-dependent systemic inflammatory responses. In summary, we show that a therapeutically targetable CD1a-dependent pathway may play a role in the systemic spread of cutaneous inflammation.

A conformation-selective monoclonal antibody against a small molecule-stabilised signalling-deficient form of TNF.

We have recently described the development of a series of small-molecule inhibitors of human tumour necrosis factor (TNF) that stabilise an open, asymmetric, signalling-deficient form of the soluble TNF trimer. Here, we describe the generation, characterisation, and utility of a monoclonal antibody that selectively binds with high affinity to the asymmetric TNF trimer-small molecule complex. The antibody helps to define the molecular dynamics of the apo TNF trimer, reveals the mode of action and specificity of the small molecule inhibitors, acts as a chaperone in solving the human TNF-TNFR1 complex crystal structure, and facilitates the measurement of small molecule target occupancy in complex biological samples. We believe this work defines a role for monoclonal antibodies as tools to facilitate the discovery and development of small-molecule inhibitors of protein-protein interactions.

Epitope determines efficacy of therapeutic anti-Tau antibodies in a functional assay with human Alzheimer Tau.

In Alzheimer's disease (AD) and other tauopathies, the cytosolic protein Tau misfolds and forms intracellular aggregates which accumulate within the brain leading to neurodegeneration. Clinical progression is tightly linked to the progressive spread of Tau pathology throughout the brain, and several lines of evidence suggest that Tau aggregates or "seeds" may propagate pathology by spreading from cell to cell in a "prion like" manner. Accordingly, blocking the spread of extracellular seeds with an antibody could be a viable therapeutic approach. However, as the structure of Tau seeds is unknown, it is only possible to rationally design therapeutic Tau antibodies by making a priori assumptions. To avoid this, we developed a robust and quantitative cell based assay and employed an unbiased screening approach to identify the antibody with the highest activity against human Tau seeds. The selected antibody (D), directed to the mid-region of Tau (amino acids 235-250), potently blocked the seeding of human AD Tau and was also fully efficacious against seeds from progressive supranuclear palsy. When we compared this antibody with previously described reference antibodies, we were surprised to find that none of these antibodies showed comparable efficacy against human pathological seeds. Our data highlight the difficulty of predicting antibody accessible epitopes on pathological Tau seeds and question the potential efficacy of some of the Tau antibodies that are currently in clinical development.

Physician and Parental Decision-Making Prior to Acute Medical Paediatric Admission.

BACKGROUND: The number of acute medical paediatric emergency admissions is rising. We undertook qualitative interviews with parents and clinicians to better understand what factors, other than the health status of the child, may influence decision making leading to emergency admission. METHODS: Semi-structured interviews were conducted with parents; clinicians working in general practice, out-of-hours or the emergency department (referring clinicians); and doctors working in acute medical paediatrics (receiving clinicians). RESULTS: Ten parents, 7 referring clinicians and 10 receiving clinicians were interviewed. Parents described "erring on the side of caution" when seeking medical opinion and one mentioned anxiety. Among themes seen among referring clinicians, "erring on the side of caution" was also identified as was managing "parental anxiety" and acting on "gut instinct". Among receiving clinicians, themes included managing parental anxiety and increasing parental expectations of the health service. CONCLUSIONS: The study of parent and referring clinician decision-making prior to a hospital admission can identify "teachable moments" where interventions might be delivered to slow or even arrest the rise in short-stay acute medical admissions in Britain and other countries. Interventions could assure parents or referring clinicians that hospital referral is not required and help clinicians understand what they perceive as "parental anxiety".

Generation and characterization of a high affinity anti-human FcRn antibody, rozanolixizumab, and the effects of different molecular formats on the reduction of plasma IgG concentration.

Rozanolixizumab (UCB7665), a humanized high-affinity anti-human neonatal Fc receptor (FcRn) monoclonal antibody (IgG4P), has been developed to reduce pathogenic IgG in autoimmune and alloimmune diseases. We document the antibody isolation and compare rozanolixizumab with the same variable region expressed in various mono-, bi- and trivalent formats. We report activity data for rozanolixizumab and the different molecular formats in human cells, FcRn-transgenic mice, and cynomolgus monkeys. Rozanolixizumab, considered the most effective molecular format, dose-dependently and selectively reduced plasma IgG concentrations in an FcRn-transgenic mouse model (no effect on albumin). Intravenous (IV) rozanolixizumab dosing in cynomolgus monkeys demonstrated non-linear pharmacokinetics indicative of target-mediated drug disposition; single IV rozanolixizumab doses (30 mg/kg) in cynomolgus monkeys reduced plasma IgG concentration by 69% by Day 7 post-administration. Daily IV administration of rozanolixizumab (initial 30 mg/kg loading dose; 5 mg/kg daily thereafter) reduced plasma IgG concentrations in all cynomolgus monkeys, with low concentrations maintained throughout the treatment period (42 days). In a 13-week toxicology study in cynomolgus monkeys, supra-pharmacological subcutaneous and IV doses of rozanolixizumab (≤ 150 mg/kg every 3 days) were well tolerated, inducing sustained (but reversible) reductions in IgG concentrations by up to 85%, with no adverse events observed. We have demonstrated accelerated natural catabolism of IgG through inhibition of IgG:FcRn interactions in mice and cynomolgus monkeys. Inhibition of FcRn with rozanolixizumab may provide a novel therapeutic approach to reduce pathogenic IgG in human autoimmune disease. Rozanolixizumab is being investigated in patients with immune thrombocytopenia (NCT02718716) and myasthenia gravis (NCT03052751).

Mortality and other outcomes after paediatric hospital admission on the weekend compared to weekday.

Mortality is higher for adults admitted to hospital and for babies born on weekends compared to weekdays. This study compares in-hospital mortality and in children admitted to hospital on weekends and weekdays. Details for all acute medical admissions to hospitals in Scotland for children aged ≤16 years between 1st January 2000 and 31st December 2013 were obtained. Death was linked to day of admission. There were 570,403 acute medical admissions and 334 children died, including 83 who died after an admission on Saturday or Sunday and 251 who died following admission between Monday and Friday. The adjusted odds ratio (aOR) for a child dying after admission on a weekend compared to weekday was 1.03 [95% CI 0.80 to 1.32]. The OR for a child admitted over the weekend requiring intensive care unit (ICU) or high dependency unit (HDU) care was 1.24 [1.16 to 1.32], but the absolute number of admissions to HDU and ICU per day were similar on weekends and weekdays. We see no evidence of increased in-hospital paediatric mortality after admission on a weekend. The increased risk for admission to ITU or HDU with more serious illness over weekends is explained by fewer less serious admissions.

Changing characteristics of hospital admissions but not the children admitted-a whole population study between 2000 and 2013.

There are increasing numbers of emergency medical paediatric admissions. Our hypothesis was that characteristics of children and details of their emergency admissions are also changing over time. Details of emergency admissions in Scotland 2000-2013 were analysed. There were 574,403 emergency admissions, median age 2.3 years. The age distribution, proportion of boys and socioeconomic status of children admitted were essentially unchanged. Emergency admissions rose by 49% from 36/1000 children per annum to 54/1000 between 2000 and 2013. Emergency admissions that were discharged on the same day rose by 186% from 8.6/1000 to 24.6/1000. The mean duration of emergency admission fell from 1.7 to 1.0 days. The odds for an emergency admission with upper respiratory infection, "viral infection", tonsillitis, bronchiolitis and lower respiratory tract infection all rose. In contrast the odds for an emergency admission with asthma and gastroenteritis fell. CONCLUSIONS: The demographics of children with emergency admissions have not changed substantially but characteristics of admissions have changed considerably, in particular admissions which are short stay and due to respiratory infection are much more common. The fall in the absolute number of children with some acute medical diagnoses suggests that the rise in admissions is not necessarily inexorable. What is Known: • Emergency admission prevalence is rising in many countries across Europe. What is New: • Our paper is the first to comprehensively analyse emergency medical paediatric admissions by exploring how characteristics of admissions and the children admitted have changed over time for a whole population. • The "take home message" is that whilst characteristics of emergency admissions have changed (e.g. number, duration of stay, readmissions, diagnoses), the characteristics of the children have not changed.

Posthemorrhagic ventricular dilatation-impact on early neurodevelopmental outcome.

OBJECTIVE: This study evaluates the impact of ventricular dilatation following severe (grades III or IV) intraventricular hemorrhage (IVH) in preterm neonates and the current practice of neurosurgical interventions in infants with posthemorrhagic ventricular dilatation (PHVD) and early neurodevelopmental outcome. STUDY DESIGN: Premature neonates born at ≤34 weeks' gestational ages with severe IVH were identified retrospectively over a 5-year period (2005 to 2009). Standard measures of ventricular dilatation on head ultrasound (HUS) were recorded. The treatment of PHVD, timing of surgery including the type of temporizing neurosurgical procedure (TNP)-either a ventricular reservoir or a subgaleal shunt-and the subsequent need for ventriculoperitoneal (VP) shunt were evaluated. Patients were retrospectively stratified to an "early" versus "late" intervention group based on HUS measures. Early intervention was defined as TNP performed when the ventricular index (VI) was >97th percentile but <97th percentile + 4 mm. Late intervention was defined as TNP performed when VI was ≥97th percentile + 4 mm. Neurodevelopmental outcomes were evaluated at 18 to 24 months. Infants followed up for neurodevelopmental testing were stratified as group A (progressive PHVD with TNP), group B (PHVD without TNP), and group C (severe IVH without PHVD). RESULTS: One hundred seventy-three preterm neonates with severe IVH were identified during the study period, of whom 139/173 (80%) developed PHVD. Of these, 54 (54/139, 39%) received TNP either early (4/54, 7%) or late (50/54, 93%). Of those who received TNP, 32/54 (59%) required subsequent VP shunt placement. Neurodevelopmental testing was available in 39/109 (36%) infants who survived to discharge. The mean ± standard deviation cognitive, motor, and language composite scores were 77 ± 14.8, 67 ± 15.2, 70 ± 13.8 for group A (n = 16/39), 90 ± 7.8, 84 ± 9.6, 82 ± 18.2 for group B (n = 12/39), and 95 ± 14.3, 86 ± 10.7, 94 ± 15.8 for group C (n = 11/39), respectively (p < 0.006 for group A versus group B and p < 0.004 for group A versus group C across all domains). Increasing ventricular dilatation was associated with adverse motor, cognitive, and language outcomes (p = 0.002) and neonates with progressive PHVD requiring a TNP were most adversely affected (p = 0.0006). There were no differences in any outcome measures between the two types of TNPs. Clinical and demographic characteristics of infants lost to follow-up were not significantly different than those available for follow-up. CONCLUSION: Increasing ventricular size adversely affects neurodevelopmental outcome in infants with PHVD.

Sacroiliac joint pain in the pediatric population.

OBJECT: The sacroiliac (SI) joint can be a pain generator in 13%-27% of cases of back pain in adults. These numbers are largely unknown for the pediatric population. In children and especially girls, development of the pelvic girdle makes the SI joint prone to misalignment. Young athletes sustain repeated stress on their SI joints, and sometimes even minor trauma can result in lasting pain that mimics radiculopathy. The authors present a series of 48 pediatric patients who were evaluated for low-back pain and were found to have SI joint misalignment as the cause of their symptoms. They were treated with a simple maneuver described in this paper that realigned their SI joint and provided significant improvement of symptoms. METHODS: A retrospective review of the electronic records identified 48 patients who were referred with primary complaints of low-back pain and were determined to have SI joint misalignment during bedside examination maneuvers described here. Three patients did not have a record of their response to treatment and were excluded. Patients were evaluated by a physical therapist and had the realignment procedure performed on the day of initial consultation. The authors collected data regarding the immediate effect of the procedure, as well as the duration of pain relief at follow-up visits. RESULTS: Eighty percent of patients experienced dramatic improvement in symptoms that had a lasting effect after the initial treatment. The majority of them were given a home exercise program, and only 2 of the 36 patients who experienced significant relief had to be treated again. Fifty-three percent of all patients had immediate and complete resolution of symptoms. Three of the 48 patients had missing data from the medical records and were excluded from computations. CONCLUSIONS: Back pain is multifactorial, and the authors' data demonstrate the potential importance of SI joint pathology. Although the technique described here for treatment of misaligned SI joints in the pediatric patients is not effective in all, the authors have observed significant improvement in 80% of cases. Often it is difficult to determine the exact cause of back pain, but when the SI joint is suspected as the primary pathology, the authors have described a simple and effective bedside treatment that should be attempted prior to the initiation of further testing and surgery.

Palliative hemispherotomy in children with bilateral seizure onset.

OBJECT: Intractable epilepsy is a significant burden on families and on the cognitive development and quality of life (QOL) of patients. Periinsular hemispherotomy (PIH) for medically intractable epilepsy can benefit patients who qualify for this procedure. The ideal hemispherotomy candidate has ipsilateral ictal and interictal epileptiform activity, unilateral MR imaging abnormalities, contralateral hemiplegia, and a normal contralateral hemisphere. However, certain patients present with a mixed picture of bilateral electroencephalography (EEG) findings and severe intractable epilepsy, prompting consideration of a more aggressive treatment approach. This report introduces the possibility of surgery for patients who normally would not meet criteria for this treatment modality. METHODS: In this retrospective chart review, the authors report on 7 patients with bilateral seizure onset noted on routine or video-EEG monitoring. A QOL phone questionnaire, based on the Quality of Life in Childhood Epilepsy tool, was administered to a parent. The authors reviewed each patient's chart for surgical complications, changes in examination, QOL, limited neuropsychological outcomes, and seizure outcomes. They also investigated each chart for MR imaging and EEG findings as well as the patient's epilepsy clinic notes for seizure semiology and frequency. RESULTS: All patients enjoyed a decrease in seizure frequency and a subjective increase in QOL after PIH. Five patients (71%) achieved Engel Class I or II seizure control. The mean follow-up was 3.64 years (2-5.3 years). One patient is now off all antiseizure medication. No patient had a decrement in Full Scale IQ on postsurgical testing, and 2 (28.5%) of 7 individuals had increased adaptive and social functioning. Postsurgical examination changes included hemiplegia and homonymous hemianopia. CONCLUSIONS: Hemispherotomy in patients with intractable epilepsy is generally reserved for individuals with unilateral epileptiform abnormalities or lesions on MR imaging. Seven patients in this study benefited from surgery despite bilateral seizure onset with improvement in seizure control and overall QOL. Thus, bilateral ictal onset does not necessarily preclude consideration for hemispherotomy in selected patients with severe medically refractory epilepsy.

Impact of epilepsy surgery on seizure control and quality of life: a 26-year follow-up study.

PURPOSE: The short-term efficacy and safety of epilepsy surgery relative to medical therapy has been established, but it remains underutilized. There is a lack of data regarding the long-term seizure-control rates and quality of life outcomes after epilepsy surgery. This study represents the longest follow-up study to date, with a mean follow-up duration of 26 years. METHODS: We studied the seizure and health-related quality of life outcomes of patients who underwent epilepsy surgery by Dr. Sidney Goldring from 1967 to 1990. Retrospective clinical chart reviews gathered perioperative data and surveys obtained follow-up data. Seizure outcome was evaluated using the Engel classification system. KEY FINDINGS: Of 361 patients, 117 (32.4%) completed follow-up interviews. Fifty-six patients (48%) were Engel class I. Mean overall Quality of Life in Epilepsy (QOLIE-31) questionnaire score for the cohort was 68.2 ± 16. Eighty percent of patients reported their overall quality of life now as being better than before surgery. Seizure freedom was associated with better quality of life. We did not observe a statistically significant association between postoperative complications and long-term outcome. Patients who underwent temporal lobe resection achieved better seizure outcomes than those who underwent other types of procedures. Astatic seizures and bilateral surgery were associated with a worse Engel class outcome. SIGNIFICANCE: Our study demonstrates that the beneficial effects of epilepsy surgery are sustained over decades, and that these beneficial effects are correlated with an improved quality of life. The confirmation of its durability makes us optimistic that the outcomes from modern epilepsy surgery will be even better and that our present enthusiasm for this treatment modality is not misplaced.

Differential effects of acute amphetamine and phencyclidine treatment and withdrawal from repeated amphetamine or phencyclidine treatment on social interaction and social memory in rats.

Although animal models based on amphetamine (AMPH) or phencyclidine (PCP) treatment have been used extensively to study the neurobiological and behavioral characteristics of schizophrenia, there are conflicting reports regarding their validity in modeling the negative symptoms and cognitive deficits of schizophrenia. The present study examined how acute AMPH or PCP treatment (Experiment 1) and withdrawal from repeated AMPH treatment (Experiment 2) or PCP treatment (Experiment 3) affects social behavior and social recognition memory in male Sprague-Dawley rats. Each subject was tested on two consecutive days. On the first day, the rats were tested four times (5 min/each) at 10-min intervals with the same partner rat (termed "AAAA" day). One day later, the rats were tested with the previous partner in the first three sessions and with a new partner rat in the final session (termed "AAAB" day). The results show that acute AMPH treatment (1.5 mg/kg, sc) significantly reduced the time spent on social interaction, but did not affect social recognition on the first day. Acute AMPH only disrupted social recognition on the second day of drug testing. In contrast, acute PCP treatment (2.0 mg/kg, sc) had no effect on time spent on social interaction, but did significantly disrupt social recognition on both days. Withdrawal from repeated AMPH (3.0 mg/kg/day for 7 days, ip) or PCP (5.0 mg/kg/twice daily for 7 days, ip) treatment did not affect social interaction or social recognition, indicating a lack of long-term detrimental effect of repeated AMPH or PCP treatment. These results suggest that acute AMPH treatment at a low dose (1.5 mg/kg) may be useful in modeling social withdrawal symptoms of schizophrenia, whereas acute PCP treatment at a similar dose range (2.0 mg/kg) may be useful in modeling the social cognitive deficit of schizophrenia.

Neurosurgical treatment of progressive posthemorrhagic ventricular dilation in preterm infants: a 10-year single-institution study.

OBJECT: Intraventricular hemorrhage (IVH) and progressive posthemorrhagic ventricular dilation (PPHVD) may result in significant neurological morbidity in preterm infants. At present, there is no consensus regarding the optimal timing or type of neurosurgical procedure to best treat PPHVD. Conflicting data exist regarding the relative risks and benefits of two commonly used temporizing neurosurgical procedures (TNPs), ventricular access devices ([VADs] or ventricular reservoirs) versus ventriculosubgaleal (VSG) shunts. This study was designed to address this issue. METHODS: This is a single-center, 10-year retrospective review of all preterm infants admitted to the St. Louis Children's Hospital neonatal intensive care unit (NICU) with Papile Grade III-IV IVH. The development of PPHVD and the requirement for and type of TNP were recorded. Rates of TNP complication, ventriculoperitoneal (VP) shunt implantation, shunt infection, and mortality rates were used to compare the efficacy and limitations of each TNP type. RESULTS: Over this 10-year interval, 325 preterm infants with Grade III-IV IVH were identified, with trends showing an increasing number of affected infants annually, and an increasing number of TNPs were required annually. Ninety-five (29.2%) of the 325 infants underwent a TNP for PPHVD (65 VADs, 30 VSG shunts). The rate of permanent VP shunt implantation for all TNPs was 72.6% (69 of 95 infants). Forty-nine (75.4%) of the 65 infants treated with VADs and 20 (66.7%) of the 30 treated with VSG shunts required VP shunts (p = 0.38). There was no statistical difference between VAD or VSG shunt with regard to TNP-related infection (p = 0.57), need for TNP revision (p = 0.16), subsequent shunt infection (p = 0.77), shunt revision rate (p = 0.58), or mortality rate (p = 0.24). CONCLUSIONS: Rates of IVH and PPHVD observed at the authors' center have increased over time. In contrast to recent literature, the results from the current study did not demonstrate a difference in complication rate or requirement for permanent VP shunt placement between VADs and VSG shunts. Definitive conclusions will require a larger, prospective trial.

Amphetamine selectively enhances avoidance responding to a less salient stimulus in rats.

This preclinical study examined the psychological processes affected by amphetamine that contribute to human psychosis. Using a novel avoidance conditioning paradigm involving two conditioned stimuli (CS) with varied salience, we found that acute amphetamine (1.5 mg/kg, i.p.) selectively enhanced avoidance responding to a less salient stimulus, but not to a salient one. These findings suggest that elevated dopaminergic activity selectively enhances the attributions of motivational salience to a less salient stimulus, a process that may bear relevance to the development of human delusional thoughts.