A new genotype of hepatitis A virus causing transient liver enzyme elevations in Mauritius-origin laboratory-housed .

Hepatitis A virus (HAV) infects humans and nonhuman primates, typically causing an acute self-limited illness. Three HAV genotypes have been described so far for humans, and three genotypes have been described for nonhuman primates. We observed transiently elevated liver enzymes in Mauritius-origin laboratory-housed macaques in Germany and were not able to demonstrate an etiology including HAV by serology and polymerase chain reaction (PCR).

Safety, Pharmacokinetic, and Pharmacodynamic Evaluation of a 2'-(2-Methoxyethyl)-D-ribose Antisense Oligonucleotide-Triantenarry -Acetyl-galactosamine Conjugate that Targets the Human Transmembrane Protease Serine 6.

Cellular uptake of antisense oligonucleotides (ASOs) is one of the main determinants of in vivo activity and potency. A significant advancement in improving uptake into cells has come through the conjugation of ASOs to triantenarry -acetyl-galactosamine (GalNAc), a ligand for the asialoglycoprotein receptor on hepatocytes. The impact for antisense oligonucleotides, which are already taken up into hepatocytes, is a 10-fold improvement in potency in mice and up to a 30-fold potency improvement in humans, resulting in overall lower effective dose and exposure levels.

Overview and considerations for the reporting of clinical pathology interpretations in nonclinical toxicology studies.

Clinical pathology reporting practices are diverse among individuals and organizations involved in nonclinical toxicology studies. Clear, informative, and consistent reporting of clinical pathology results increases their value and avoids misinterpretation, resulting in decreased drug development costs. In recent years, certain common practices in clinical pathology reporting have been embraced by industry leaders and more consistently utilized across the pharmaceutical industry.

Interpretative considerations for clinical pathology findings in nonclinical toxicology studies.

The interpretation of clinical pathology results from nonclinical safety studies is a fundamental component in hazard identification of new drug candidates. The ever-increasing complexity of nonclinical safety studies and sophistication of modern analytical methods have made the interpretation of clinical pathology information by a highly trained subject matter expert imperative. Certain interpretive techniques are particularly effective in the identification and characterization of clinical pathology effects.

Current Practices and Challenges in Method Validation.

Method validation is a cornerstone on which biomarker development and utilization rest. However, given the abundance of biomarker candidates that are being identified and characterized, validation of these entities for the use in nonclinical studies can be complex. The objective of this continuing education course was to review current practices and challenges encountered during the validation of methods for the analysis of novel biomarkers.

Best practices for veterinary toxicologic clinical pathology, with emphasis on the pharmaceutical and biotechnology industries.

The purpose of this paper by the Regulatory Affairs Committee (RAC) of the American Society for Veterinary Clinical Pathology (ASVCP) is to review the current regulatory guidances (eg, guidelines) and published recommendations for best practices in veterinary toxicologic clinical pathology, particularly in the pharmaceutical and biotechnology industries, and to utilize the combined experience of ASVCP RAC to provide updated recommendations. Discussion points include (1) instrumentation, validation, and sample collection, (2) routine laboratory variables, (3) cytologic laboratory variables, (4) data interpretation and reporting (including peer review, reference intervals and statistics), and (5) roles and responsibilities of clinical pathologists and laboratory personnel. Revision and improvement of current practices should be in alignment with evolving regulatory guidance documents, new technology, and expanding understanding and utility of clinical pathology.

Regulatory forum opinion piece: blind reading of histopathology slides in general toxicology studies.

With the intention of reducing bias, a recent European Food Safety Authority draft guidance document included a recommendation for blinded evaluation of histopathology slides in general toxicology studies (EFSA 2011). Although blinding as to treatment status reduces bias in many types of scientific experiment and is sometimes also appropriate in toxicologic pathology (Holland and Holland 2011), it is most unlikely to help achieve the overall goal of improved human safety when used for routine histopathology evaluation of tissues in general toxicology studies. This is the case because (1) blinding is not applicable to the inductive reasoning process used to identify test article effects in the tissues and would dramatically reduce the chances of these being successfully identified; and (2) in any case, the bias that would be reduced by blinding is actually a bias favoring diagnosis of a toxicological hazard and a conservative safety evaluation, which is appropriate in this context.

Effects of hepatic drug-metabolizing enzyme induction on clinical pathology parameters in animals and man.

Hepatic drug-metabolizing enzyme (DME) induction is an adaptive response associated with changes in preclinical species; this response can include increases in liver weight, hepatocellular hyperplasia and hypertrophy, and upregulated tissue expression of DMEs. Effects of DME induction on clinical pathology markers of hepatobiliary injury and function in animals as well as humans are not well established. This component of a multipart review of the comparative pathology of xenobiotically mediated induction of hepatic metabolizing enzymes reviews pertinent data from retrospective and prospective preclinical and clinical studies.

Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta.

Passive immunization with an antibody directed against the N terminus of amyloid beta (Abeta) has recently been reported to exacerbate cerebral amyloid angiopathy (CAA)-related microhemorrhage in a transgenic animal model. Although the mechanism responsible for the deleterious interaction is unclear, a direct binding event may be required. We characterized the binding properties of several monoclonal anti-Abeta antibodies to deposited Abeta in brain parenchyma and CAA.

Use of the Cell-Dyn 3500 to predict leukemic cell lineage in peripheral blood of dogs and cats.

Background: Morphology and cytochemistry are the foundation for classification of leukemias in dogs and cats. Advances in automated hematology instrumentation, immunophenotyping, cytogenetics, and molecular biology are significantly improving our ability to recognize and classify spontaneous myeloproliferative and lymphoproliferative disorders.

Objective: The purpose of this study was to assess the utility of flow cytometry-based light scatter patterns provided by the Cell-Dyn 3500 (CD3500) automated hematology analyzer to predict the lineage of leukemic cells in peripheral blood of dogs and cats.