Dupilumab Efficacy in Steroid-Dependent Severe Asthma by Baseline Oral Corticosteroid Dose.

Background: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4/-13, key and central drivers of type 2 inflammation in multiple diseases. In the phase 3 LIBERTY ASTHMA VENTURE (VENTURE) study (NCT02528214), dupilumab versus placebo reduced oral corticosteroid (OCS) dose and improved clinical outcomes in patients with OCS-dependent severe asthma. Dupilumab efficacy in patients with varying disease burden (defined by baseline OCS dose) has not been assessed.

Sustained reduction of serum neurofilament light chain over 7 years by alemtuzumab in early relapsing-remitting MS.

Background: Alemtuzumab efficacy and safety was demonstrated in CARE-MS I and extension studies (CAMMS03409; TOPAZ).

Objective: Evaluate serum neurofilament light chain (sNfL) in CARE-MS I patients and highly active disease (HAD) subgroup, over 7 and 2 years for alemtuzumab and subcutaneous interferon beta-1a (SC IFNB-1a), respectively.

Methods: Patients received SC IFNB-1a 44 µg 3×/week or alemtuzumab 12 mg/day at baseline and month 12, with further as-needed 3-day courses.

A double-blind, randomized trial to evaluate the pharmacokinetics and tolerability of 30 or 40 mg/d oral olanzapine relative to 20 mg/d oral olanzapine in stable psychiatric subjects.

Background: Prescription monitoring in the United States suggests that oral olanzapine is prescribed in doses that exceed the approved range of 5 to 20 mg/d.

Objective: In this double-blind, randomized study, the pharmacokinetics and tolerability of higher-dose (30 or 40 mg/d) olanzapine were examined relative to the highest approved dose (20 mg/d) among non-treatment-resistant patients with psychiatric illnesses.

Methods: After a 10-day period in which all patients were stabilized on 20 mg/d olanzapine, 37 patients with schizophrenia, schizoaffective disorder, or bipolar I disorder were randomized to receive treatment with olanzapine 20 mg/d for 20 days (group A, n=12), 30 mg/d for 10 days followed by 40 mg/d for 10 days (group B, n=11), or 40 mg/d for 20 days (group C, n=14).

Reelin promoter hypermethylation in schizophrenia.

Reelin mRNA and protein levels are reduced by approximately 50% in various cortical structures of postmortem brain from patients diagnosed with schizophrenia or bipolar illness with psychosis. In addition, the mRNA encoding the methylating enzyme, DNA methyltransferase 1, is up-regulated in the same neurons that coexpress reelin and glutamic acid decarboxylase 67. We have analyzed the extent and pattern of methylation within the CpG island of the reelin promoter in genomic DNA isolated from cortices of schizophrenia patients and nonpsychiatric subjects.

Histone deacetylase inhibitors decrease reelin promoter methylation in vitro.

We investigated the effects of agents that induce reelin mRNA expression in vitro on the methylation status of the human reelin promoter in neural progenitor cells (NT2). NT2 cells were treated with the histone deacetylase inhibitors, trichostatin A (TSA) and valproic acid (VPA), and the methylation inhibitor aza-2'-deoxycytidine (AZA) for various times. All three drugs reduced the methylation profile of the reelin promoter relative to untreated cells.

Differential effects of removing the glucose or saccharin components of a glucose-saccharin mixture in a successive negative contrast paradigm.

When rats experience an unexpected decrease in reward value, e.g., from 32% sucrose to 4% sucrose, consummatory behavior abruptly decreases to a level below control subjects that only experience the lesser reward, a phenomenon known as Successive Negative Contrast (SNC).

Neonatal lesions of the ventral hippocampal formation alter GABA-A receptor subunit mRNA expression in adult rat frontal pole.

Background: Gamma-aminobutyric acid (GABA)-ergic function is altered in schizophrenia. Of particular interest is the altered central nervous system expression of GABA-A receptor subunits, as changes in subunit expression account for recognized differences in mammalian brain function making them inviting targets for novel psychotropic agents. Excitotoxic neonatal lesions of the ventral hippocampal formation (NVHL) in rats reproduce numerous aspects of schizophrenia, including decreased mRNA expression of the GABA synthesizing enzyme glutamic acid decarboxylase-67, though their impact on subunit expression is unknown.

Evidence for zolpidem-induced hyperphagia, but not anxiolysis, in a successive negative contrast paradigm.

Zolpidem is an imidazopyridine which binds to certain benzodiazepine receptor types with varying degrees of affinity. The effect of zolpidem on successive negative contrast was investigated in three experiments. In each experiment, a contrast group was given brief access to 32% sucrose for 10 days, then shifted to 4% sucrose for 2 days; a procedure that elicits anxiety primarily on the second postshift day.

Neonatal lesions of the ventral hippocampal formation disrupt neuroendocrine responses to auditory stress in the adult rat.

Lesioning the ventral hippocampal formation (vHF) in the neonatal rat with an excitotoxin replicates several features of schizophrenia. Similar lesions in the adult rat disrupt the normal constraint of neuroendocrine responses to environmental stressors, which is of potential interest because the enhanced HPA axis and antidiuretic hormone activity in schizophrenia is linked to acute stress and hippocampal formation (HF) pathology. In the current study, we investigated the effects of neonatal ventral hippocampal formation lesions (NVHFL) on plasma adrenocorticotropin hormone (ACTH) and arginine vasopressin (AVP) responses following a 2-min acoustic stressor in the adult rat.

What is the functional significance of hippocampal pathology in schizophrenia?

The hippocampal formation (HF) is one of the brain structures most consistently altered in schizophrenia, yet the contribution of HF pathology to severe mental illness is poorly understood. We present evidence that our current ignorance is attributable to the fact that the anterior HF is heavily involved in schizophrenia but has been inadequately examined by schizophrenia investigators. We propose that the anterior HF in humans, and its counterpart in rodents (ventral HF), constrain diverse responses to psychological stimuli and that disruption of this function contributes to schizophrenia.

GABAergic cortical neuron chromatin as a putative target to treat schizophrenia vulnerability.

Inhibitory GABAergic interneurons of prefrontal cortex (PFC) appear to play an important role in the regulation of intermittent pyramidal neuron columnary firing and in the neuronal plasticity that mediate cognitive functions. In schizophrenia (SZ), cognitive defects and dysfunctions in pyramidal neuronal columnary firing appear to depend on abnormalities of GABAergic neurons. These abnormalities include a decrease of GAD67 and reelin expression, which result in a reduction of cortical inhibitory input to spine postsynaptic densities as a result of the decrease of GABA concentration at the synaptic cleft, and of neurotrophic stimuli as a result of the decrease of reelin secreted into the extracellular matrix.