Dual-Toxin ("Bivalent") Infant Botulism in California, 1976-2020: Epidemiologic, Clinical, and Laboratory Aspects.

Objective: To assess the consequences of infant botulism that result from Clostridium botulinum strains that produce 2 botulinum toxin serotypes, termed "bivalent."

Study Design: Epidemiologic investigations used a standard questionnaire. Clostridium botulinum strains were isolated by standard methods.

Safety and immunogenicity of investigational recombinant botulinum vaccine, rBV A/B, in volunteers with pre-existing botulinum toxoid immunity.

Objectives: We undertook an open-label, uncontrolled study of investigational recombinant botulinum vaccine for botulinum neurotoxin (BoNT) serotypes A and B (rBV A/B) to assess its safety and immunogenicity in healthy volunteers who had been previously immunized with investigational pentavalent botulinum toxoid. Study participants who wished to do so could donate their hyperimmune plasma for production of Human Botulism Immune Globulin Intravenous (BIG-IV, BabyBIG®).

Study Design: A single 0.

In vivo modulation of polo-like kinases supports a key role for PLK2 in Ser129 α-synuclein phosphorylation in mouse brain.

α-Synuclein is the major component of Lewy bodies. α-Synuclein phosphorylated at Ser 129 (Phospho-α-Syn) is the most common synuclein modification observed in Parkinson's disease pathology and transgenic animal models. Polo-like kinase 2 (PLK2) was previously proposed as an important kinase in α-synuclein phosphorylation at Ser129.

Selective and brain-permeable polo-like kinase-2 (Plk-2) inhibitors that reduce α-synuclein phosphorylation in rat brain.

Polo-like kinase-2 (Plk-2) has been implicated as the dominant kinase involved in the phosphorylation of α-synuclein in Lewy bodies, which are one of the hallmarks of Parkinson's disease neuropathology. Potent, selective, brain-penetrant inhibitors of Plk-2 were obtained from a structure-guided drug discovery approach driven by the first reported Plk-2-inhibitor complexes. The best of these compounds showed excellent isoform and kinome-wide selectivity, with physicochemical properties sufficient to interrogate the role of Plk-2 inhibition in vivo.

Discovery of (R)-4-cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline (ELND006) and (R)-4-cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline (ELND007): metabolically stable γ-secretase Inhibitors that selectively inhibit the production of amyloid-β over Notch.

Herein, we describe our strategy to design metabolically stable γ-secretase inhibitors which are selective for inhibition of Aβ generation over Notch. We highlight our synthetic strategy to incorporate diversity and chirality. Compounds 30 (ELND006) and 34 (ELND007) both entered human clinical trials.

Development of an enzyme-linked immunosorbent assay (ELISA) to measure the level of tyrosine hydroxylase protein in brain tissue from Parkinson's disease models.

Tyrosine hydroxylase (TH) catalyses the rate-limiting step in the biosynthesis of catecholamines. TH expression is regulated in a tissue-specific manner during neuronal development and differentiation. Because of its key regulatory role in central and peripheral catecholamine synthesis, TH is associated with the pathogenesis of several neurological and psychiatric diseases, including Parkinson's disease, dystonia, schizophrenia, affective disorders, and cardiovascular diseases.

Design and synthesis of highly selective, orally active Polo-like kinase-2 (Plk-2) inhibitors.

Polo-like kinase-2 (Plk-2) is a potential therapeutic target for Parkinson's disease and this Letter describes the SAR of a series of dihydropteridinone based Plk-2 inhibitors. By optimizing both the N-8 substituent and the biaryl region of the inhibitors we obtained single digit nanomolar compounds such as 37 with excellent selectivity for Plk-2 over Plk-1. When dosed orally in rats, compound 37 demonstrated a 41-45% reduction of pS129-α-synuclein levels in the cerebral cortex.

Discovery of 4-alkylamino-7-aryl-3-cyanoquinoline LRRK2 kinase inhibitors.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with familial Parkinson's disease (PD). The kinase activity of this complex protein is increased by pathogenic mutations. Inhibition of LRRK2 kinase activity has therefore emerged as a promising approach for the treatment of PD.

Development and validation of immunoassays to quantify the half-antibody exchange of an IgG4 antibody, natalizumab (Tysabri®) with endogenous IgG4.

Natalizumab is a humanized IgG4 monoclonal antibody which binds human α4 integrin and is approved for treatment of multiple sclerosis and Crohn's disease. Assessment of the in vivo disposition of natalizumab presents a unique assay development challenge due to the ability of human IgG4 antibodies to undergo half-antibody exchange in vivo. Such exchange generates IgG4 molecules of mixed specificity comprising a natalizumab heavy-light chain pair coupled to an IgG4 heavy-light chain pair of unknown specificity.

Amyloid precursor protein selective gamma-secretase inhibitors for treatment of Alzheimer's disease.

Introduction: Inhibition of gamma-secretase presents a direct target for lowering Aβ production in the brain as a therapy for Alzheimer's disease (AD). However, gamma-secretase is known to process multiple substrates in addition to amyloid precursor protein (APP), most notably Notch, which has limited clinical development of inhibitors targeting this enzyme. It has been postulated that APP substrate selective inhibitors of gamma-secretase would be preferable to non-selective inhibitors from a safety perspective for AD therapy.

Design of an orally efficacious hydroxyethylamine (HEA) BACE-1 inhibitor in a preclinical animal model.

In this Letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing 16 which lowers Αβ by 28% and 32% in the cortex and CSF, respectively, in the preclinical wild type Hartley guinea pig animal model when dosed orally at 30mpk BID for 2.5days.

A single ascending dose study of bapineuzumab in patients with Alzheimer disease.

The safety, tolerability, and pharmacokinetics (PKs) of bapineuzumab (AAB-001), a humanized monoclonal antibody to amyloid beta, were evaluated in patients with mild-to-moderate Alzheimer disease in a phase 1, randomized, third-party unblinded, placebo-controlled, single ascending dose trial. Thirty patients received bapineuzumab infusion of 0.5, 1.

Polo-like kinase 2 (PLK2) phosphorylates alpha-synuclein at serine 129 in central nervous system.

Several neurological diseases, including Parkinson disease and dementia with Lewy bodies, are characterized by the accumulation of alpha-synuclein phosphorylated at Ser-129 (p-Ser-129). The kinase or kinases responsible for this phosphorylation have been the subject of intense investigation. Here we submit evidence that polo-like kinase 2 (PLK2, also known as serum-inducible kinase or SNK) is a principle contributor to alpha-synuclein phosphorylation at Ser-129 in neurons.

Antibody capture of soluble Abeta does not reduce cortical Abeta amyloidosis in the PDAPP mouse.

Background: In vivo administration of antibodies against the amyloid-beta (Abeta) peptide has been shown to reduce and reverse the progressive amyloidosis that develops in a variety of mouse models of Alzheimer's disease (AD). This work has been extended to clinical trials where subsequent autopsy cases of AD subjects immunized against Abeta showed similar reductions in parenchymal amyloid plaques, suggesting this approach to reduce neuropathology in man is feasible.

Objective: Multiple hypotheses have been advanced to explain how anti-Abeta antibodies may lower amyloid burden.

Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP Transgenic Mice.

The aspartyl protease beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) initiates processing of amyloid precursor protein (APP) into amyloid beta (Abeta) peptide, the major component of Alzheimer disease (AD) plaques. To determine the role that BACE1 plays in the development of Abeta-driven AD-like pathology, we have crossed PDAPP mice, a transgenic mouse model of AD overexpressing human mutated APP, onto mice with either a homozygous or heterozygous BACE1 gene knockout. Analysis of PDAPP/BACE(-/-) mice demonstrated that BACE1 is absolutely required for both Abeta generation and the development of age-associated plaque pathology.

Active beta-amyloid immunization restores spatial learning in PDAPP mice displaying very low levels of beta-amyloid.

The behavioral and biochemical impact of active immunization against human beta-amyloid (Abeta) was assessed using male transgenic (Tg) mice overexpressing a human mutant amyloid precursor protein (heterozygous PDAPP mice) and littermate controls. Administration of aggregated Abeta42 occurred at monthly intervals from 7 months ("prevention") or 11 months ("reversal"), followed by double-blind behavioral training at 16 months on a cued task, then serial spatial learning in a water maze. Using a 2 x 2 design, with Abeta42 adjuvanted with MPL-AF (adjuvant formulation of monophosphoryl lipid A) or MPL-AF alone, PDAPP mice were impaired compared with non-Tg littermates on two separate measures of serial spatial learning.

Distribution of Abeta peptide in whole blood.

The measurement of amyloid beta peptides (Abeta) in blood and plasma is expected to be a useful biomarker as potential therapeutics designed to lower Abeta peptide enter clinical trials. Many reports have suggested that Abeta could bind to substances in blood that may influence the recovery of Abeta peptide in plasma, its detection by conventional ELISAs or the actual turnover and half-life of the peptide in blood. In this study we describe a process for analyzing total Abeta in whole blood and plasma using denaturing solid-phase extraction followed by reverse-phase HPLC linked to ELISA.

Beta-amyloid immunotherapy prevents synaptic degeneration in a mouse model of Alzheimer's disease.

Alzheimer's disease neuropathology is characterized by key features that include the deposition of the amyloid beta peptide (Abeta) into plaques, the formation of neurofibrillary tangles, and the loss of neurons and synapses in specific brain regions. The loss of synapses, and particularly the associated presynaptic vesicle protein synaptophysin in the hippocampus and association cortices, has been widely reported to be one of the most robust correlates of Alzheimer's disease-associated cognitive decline. The beta-amyloid hypothesis supports the idea that Abeta is the cause of these pathologies.

Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer's disease-like neuropathology.

Transgenic PDAPP mice, which express a disease-linked isoform of the human amyloid precursor protein, exhibit CNS pathology that is similar to Alzheimer's disease. In an age-dependent fashion, the mice develop plaques containing beta-amyloid peptide (Abeta) and exhibit neuronal dystrophy and synaptic loss. It has been shown in previous studies that pathology can be prevented and even reversed by immunization of the mice with the Abeta peptide.

The role of osteoclast differentiation in aseptic loosening.

The major cause of orthopaedic implant loosening is thought to be accelerated osteoclastic bone resorption due to the action of cytokines produced in response to phagocytosis of implant-derived wear particles. This accelerated osteoclastic bone resorption could be due to increases in any of the following processes: recruitment of osteoclast precursors to the local microenvironment, differentiation of precursors into mature multinucleated osteoclasts. activation of mature osteoclasts, and/or survival of osteoclasts.

Encapsulation in biodegradable microparticles enhances serum antibody response to parenterally-delivered beta-amyloid in mice.

Poly(lactide-co-glycolide) (PLG) microspheres were tested as a parenteral delivery system for human beta-amyloid (1-42) (Abeta), a potential immunotherapeutic undergoing assessment in Phase 1 studies for Alzheimer's disease (AD). Abeta was successfully encapsulated in PLG microspheres of average sizes of 3 or 15 microm diameter. Swiss Webster (SW) mice were injected by the sub-cutaneous (s.

BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles in the brain. The major components of plaque, beta-amyloid peptides (Abetas), are produced from amyloid precursor protein (APP) by the activity of beta- and gamma-secretases. beta-secretase activity cleaves APP to define the N-terminus of the Abeta1-x peptides and, therefore, has been a long- sought therapeutic target for treatment of AD.

Titanium particles stimulate bone resorption by inducing differentiation of murine osteoclasts.

Background: Loosening of orthopaedic implants is mediated by cytokines that elicit bone resorption and are produced in response to phagocytosis of implant-derived wear particles. This accelerated bone resorption could be due to increased osteoclastic activity, survival, or differentiation. Although a number of in vitro studies have shown that wear particles increase osteoclastic activity, the increase was less than twofold in all cases.

Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain.

Converging lines of evidence implicate the beta-amyloid peptide (Ass) as causative in Alzheimer's disease. We describe a novel class of compounds that reduce A beta production by functionally inhibiting gamma-secretase, the activity responsible for the carboxy-terminal cleavage required for A beta production. These molecules are active in both 293 HEK cells and neuronal cultures, and exert their effect upon A beta production without affecting protein secretion, most notably in the secreted forms of the amyloid precursor protein (APP).

Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease.

One hallmark of Alzheimer disease is the accumulation of amyloid beta-peptide in the brain and its deposition as plaques. Mice transgenic for an amyloid beta precursor protein (APP) mini-gene driven by a platelet-derived (PD) growth factor promoter (PDAPP mice), which overexpress one of the disease-linked mutant forms of the human amyloid precursor protein, show many of the pathological features of Alzheimer disease, including extensive deposition of extracellular amyloid plaques, astrocytosis and neuritic dystrophy. Active immunization of PDAPP mice with human amyloid beta-peptide reduces plaque burden and its associated pathologies.