Human selection bias drives the linear nature of the more ground truth effect in explainable deep learning optical coherence tomography image segmentation.

Supervised deep learning (DL) algorithms are highly dependent on training data for which human graders are assigned, for example, for optical coherence tomography (OCT) image annotation. Despite the tremendous success of DL, due to human judgment, these ground truth labels can be inaccurate and/or ambiguous and cause a human selection bias. We therefore investigated the impact of the size of the ground truth and variable numbers of graders on the predictive performance of the same DL architecture and repeated each experiment three times.

Cynomolgus monkey's retina volume reference database based on hybrid deep learning optical coherence tomography segmentation.

Cynomolgus monkeys (Macaca fascicularis) are commonly used in pre-clinical ocular studies. However, studies that report the morphological features of the macaque retina are based only on minimal sample sizes; therefore, little is known about the normal distribution and background variation. This study was conducted using optical coherence tomography (OCT) imaging to investigate the variations in retinal volumes of healthy cynomolgus monkeys and the effects of sex, origin, and eye side on the retinal volumes to establish a comprehensive reference database.

Cynomolgus monkey's choroid reference database derived from hybrid deep learning optical coherence tomography segmentation.

Cynomolgus monkeys exhibit human-like features, such as a fovea, so they are often used in non-clinical research. Nevertheless, little is known about the natural variation of the choroidal thickness in relation to origin and sex. A combination of deep learning and a deterministic computer vision algorithm was applied for automatic segmentation of foveolar optical coherence tomography images in cynomolgus monkeys.

Retinal Features in Cynomolgus Macaques () Assessed by Using Scanning Laser Ophthalmoscopy and Spectral Domain Optical Coherence Tomography.

Cynomolgus macaques are an important and commonly used species in preclinical toxicology studies, but structural reports of in vivo retinal findings are rare in this species. The purpose of this study was to diminish this gap and document optical coherence tomography and scanning laser ophthalmoscopy imaging data in the healthy posterior pole of cynomolgus monkeys' eyes at predose examinations. The current study is a retrospective assessment of baseline spectral domain OCT data obtained from the 768 eyes of 384 cynomolgus monkeys (192 males and 192 females) of Mauritian origin.

Macular thickness measurements of healthy, naïve cynomolgus monkeys assessed with spectral-domain optical coherence tomography (SD-OCT).

The purpose of this study was to measure central macular thickness in an unprecedented number of cynomolgus monkeys. Macular thickness was measured with Heidelberg spectral-domain OCT in 320 eyes of healthy and treatment-naïve cynomolgus monkeys (80 males and 80 females). The macula was successfully measured in all 320 eyes.

Drug-induced Obstructive and Retrograde Nephropathy Associated with α2u-globulin in Male Rats.

The chemically induced accumulation of α2u-globulin protein in male rats causes specific renal lesions and subsequent nephropathy. Herein, we report additional parallel findings in the kidney of male rats consistent with obstructive and retrograde nephropathy. Kidney and urinary bladder samples were evaluated from Wistar rats treated with RG7129 for 2 week and 8 week and from an 8-week mechanistic study using females, intact and castrated males.

Comparative assessment of immune complex-mediated hypersensitivity reactions with biotherapeutics in the non-human primate: Critical parameters, safety and lessons for future studies.

With the emergence of novel biotherapeutic formats and immunostimulatory biotherapeutics in cancer immunotherapy, an understanding of immune-complex (IC) mediated hypersensitivity reactions in toxicology studies - and their differentiation from pharmacology - remains key to the preclinical evaluation of these drugs. In this review we provide an in-depth evaluation and comparison of case examples where IC-mediated hypersensitivity reactions were observed in cynomolgus monkeys. We provide details of the parameters evaluated in each study to substantiate and guide the interpretation of these findings.

Inflammation and immunogenicity limit the utility of the rabbit as a nonclinical species for ocular biologic therapeutics.

The nonclinical safety evaluation of therapeutic drug candidates is commonly conducted in two species (rodent and non-rodent) in keeping with international health authority guidance. Biologic drugs typically have restricted species cross-reactivity, necessitating the evaluation of safety in non-human primates and thus limiting the utility of lower order species. Safety studies of cross-reactive ocular biologic drug candidates have been conducted in rabbits as a second toxicology species, despite the fact that rabbits are not a rodent species.

Absence of central nervous system and hypothermic effects after single oral administration of high doses of oseltamivir in the rat.

Oseltamivir is widely used for the treatment and prophylaxis of influenza. Renewed interest in the central nervous system (CNS) tolerability profile of oseltamivir has been triggered by the reports of neuropsychiatric adverse events in patients with influenza. In addition, a recent pre-clinical study in rodents suggested a hypothermic effect of oseltamivir.

Gene expression-based in vivo and in vitro prediction of liver toxicity allows compound selection at an early stage of drug development.

We have analyzed gene expression and histopathology of rat liver treated with a histamine-3 receptor inverse agonist under development for the treatment of obesity 24 h after a single acute administration. While histopathology did not identify a clear liver toxicity, analysis of gene changes strongly suggested the development of toxicity. This prediction was confirmed in a 2-week repeat-dose rat study where prominent liver pathology occurred, while gene changes that lead to the prediction persisted.

5-hydroxyindole-2-carboxylic acid amides: novel histamine-3 receptor inverse agonists for the treatment of obesity.

Obesity is a major risk factor in the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease, and cancer. Several pieces of evidence across different species, including primates, underscore the implication of the histamine 3 receptor (H(3)R) in the regulation of food intake and body weight and the potential therapeutic effect of H(3)R inverse agonists. A pharmacophore model, based on public information and validated by previous investigations, was used to design several potential scaffolds.

Age-dependent cognitive decline and amygdala pathology in alpha-synuclein transgenic mice.

Intraneuronal alpha-synuclein (alphaSYN) inclusions constitute the hallmark lesions of a number of neurodegenerative diseases, including Parkinson's disease and dementia with Lewy bodies. In a transgenic mouse model expressing mutant [A30P]alphaSYN under control of the pan-neuronal Thy1 promoter, motor impairment became significant beyond 17 months of age. Cognitive performance was measured in the Morris water maze and upon fear conditioning.

Distribution of GABAergic neurons in the striatum of amygdala-kindled rats: an immunohistochemical and in situ hybridization study.

A large body of experimental evidence suggests that the basal ganglia circuitry may be part of a remote control system modulating the spread of epileptic seizures. In the kindling model of temporal lobe epilepsy, this endogenous inhibitory control mechanism seems to be impaired. Neurochemical and neurophysiological studies have indicated that the activity of the GABAergic projection from the striatum to the substantia nigra pars reticulata is reduced in kindled rats, but the exact mechanisms involved in this observation are not known.

Amygdala-kindling does not induce a persistent loss of GABA neurons in the substantia nigra pars reticulata of rats.

GABAergic inhibition of the substantia nigra pars reticulata (SNR) has been shown to suppress seizures in most models of epilepsy, including the amygdala-kindling model of temporal lobe epilepsy (TLE). A dysfunction of this seizure gating mechanism of the SNR may lead to facilitation of seizure propagation in such models. In post-status epilepticus models of TLE, GABAergic neurons in the SNR are damaged, but it is not known whether such damage also occurs in kindling.