Deep Learning-Based Spermatogenic Staging in Tissue Sections of Cynomolgus Macaque Testes.

The indirect assessment of adverse effects on fertility in cynomolgus monkeys requires that tissue sections of the testis be microscopically evaluated with awareness of the stage of spermatogenesis that a particular cross-section of a seminiferous tubule is in. This difficult and subjective task could very much benefit from automation. Using digital whole slide images (WSIs) from tissue sections of testis, we have developed a deep learning model that can annotate the stage of each tubule with high sensitivity, precision, and accuracy. The model was validated on six WSI using a six-stage spermatogenic classification system. Whole slide images contained an average number of 4938 seminiferous tubule cross-sections. On average, 78% of these tubules were staged with 29% in stage I-IV, 12% in stage V-VI, 4% in stage VII, 19% in stage VIII-IX, 18% in stage X-XI, and 17% in stage XII. The deep learning model supports pathologists in conducting a stage-aware evaluation of the testis. It also allows derivation of a stage-frequency map. The diagnostic value of this stage-frequency map is still unclear, as further data on its variability and relevance need to be generated for testes with spermatogenic disturbances.

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

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). HAV is a rare pathogen in cynomolgus macaques, and since all employees were routinely vaccinated against HAV, it was not a part of the routine vaccination and screening program. A deep sequencing approach identified a new HAV genotype (referred to as Simian_HAV_Macaca/Germany/Mue-1/2022) in blood samples from affected animals. This HAV was demonstrated by reverse transcription PCR in blood and liver and by in situ hybridization in liver, gall bladder, and septal ducts. A commercial vaccine was used to protect animals from liver enzyme elevation. The newly identified simian HAV genotype demonstrates 80% nucleotide sequence identity to other simian and human HAV genotypes. There was deeper divergence between Simian_HAV_Macaca/Germany/Mue-1/2022 and other previously described HAVs, including both human and simian viruses. In situ hybridization indicated persistence in the biliary epithelium up to 3 months after liver enzymes were elevated. Vaccination using a commercial vaccine against human HAV prevented reoccurrence of liver enzyme elevations. Because available assays for HAV did not detect this new HAV genotype, knowledge of its existence may ameliorate potential significant epidemiological and research implications in laboratories globally.

Naked (N) mutant mice carry a nonsense mutation in the homeobox of Hoxc13.

Loss of function mutations in HOXC13 have been associated with Ectodermal Dysplasia-9, Hair/Nail Type (ECTD9) in consanguineous families, characterized by sparse to complete absence of hair and nail dystrophy. Here we characterize the spontaneous mouse mutation Naked (N) as a terminal truncation in the Hoxc13 (homeobox C13) gene. Similar to previous reports for homozygous Hoxc13 knock-out (KO) mice, homozygous N/N mice exhibit generalized alopecia with abnormal nails and a short lifespan. However, in contrast to Hoxc13 heterozygous KO mice, N/+ mice show generalized or partial alopecia, associated with loss of hair fibres, along with normal lifespan and fertility. Our data point to a lack of nonsense-mediated Hoxc13 transcript decay and the presence of the truncated mutant protein in N/N and N/+ hair follicles, thus suggesting a dominant-negative mutation. To our knowledge, this is the first report of a semi-dominant and potentially dominant-negative mutation affecting Hoxc13/HOXC13. Furthermore, recreating the N mutant allele in mice using CRISPR/Cas9-mediated genome editing resulted in the same spectrum of deficiencies as those associated with the spontaneous Naked mutation, thus confirming that N is indeed a Hoxc13 mutant allele. Considering the low viability of the Hoxc13 KO mice, the Naked mutation provides an attractive new model for studying ECTD9 disease mechanisms.

Does Geographical Origin of Long-Tailed Macaques (Macaca fascicularis) Matter in Drug Safety Assessment?: A Literature Review and Proposed Conclusion.

Long-tailed macaques are the predominant nonhuman primate species for the nonclinical safety testing of biopharmaceuticals. This species comprises 9 subspecies with Macaca fascicularis fascicularis naturally occurring in Southeast Asia. Since the 17th century, M. f. fascicularis also occurs on Mauritius. Cynomolgus macaques do not naturally occur in China, but are bred in many farms across the country. The current shortage in animal supply raises the question whether geographical animal origin matters and if animals from different geographical regions can be combined on a drug development program or even a single experiment. This article reviews geographical animal origin in relation to selected endpoints that are relevant in nonclinical drug safety testing. Animals from different countries within Asia mainland do not appear to show any meaningful difference. Very little data are available for animals from Asia island. Mauritian animals show consistent differences from Asian animals in several clinical and anatomical pathology parameters. For developmental parameters, animals from Mauritius and Asia are comparable with the exception that Mauritian animals mature faster. In the authors' view, differences between the geographical clusters can be accounted for as long as baseline and reference data are available.

International Harmonization of Nomenclature and Diagnostic Criteria (INHAND): Non-proliferative and Proliferative Lesions of the Non-human Primate (M. fascicularis).

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions Project (www.toxpath.org/inhand.asp) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in most tissues and organs from the nonhuman primate used in nonclinical safety studies. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. Relevant infectious and parasitic lesions are included as well. A widely accepted and utilized international harmonization of nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists.

Range of Neurological Signs in Cynomolgus Monkeys After Intrathecal Bolus Administration of Antisense Oligonucleotides.

Intrathecal (IT) dosing (ie, injection into the subarachnoidal space at the lumbar region) is a common route of administration in cynomolgus monkey preclinical safety studies conducted for antisense oligonucleotides (ASO) that target central nervous system diseases. Herein we report on neurological signs that have been observed in 28 IT studies conducted in 1,016 cynomolgus monkeys. Neurological signs were classified into 5 groups: (1) A nonadverse transient absence of lower spinal reflexes. This observation occurred at low incidence in nontreated animals and in those that were injected artificial cerebrospinal fluid. The incidence increased in animals that were injected an ASO. Reflexes were present again at 24 hours or 48 hours after dosing. The incidence appeared to increase with dose. (2) Test-article-related adverse muscle tremor or muscle spasticity occurring during the injection procedure or immediately thereafter. In one-third of animals this finding responded to treatment with diazepam, in two-third it required euthanasia. (3) Neurological findings occurring between 30 minutes and 4 hours after dosing were characterized by any combination of ataxia, paresis, nystagmus, urinary incontinence, or muscle tremor. Those conditions either spontaneously resolved or they slowly worsened, eventually resulting in a poor general condition. (4) Neurological findings due to spinal cord injury were characterized by rapidly progressing paralysis of hind limbs. Magnetic resonance imaging revealed a focal hyperintense lesion, indicative of spinal cord necrosis. (5) Test-article-related adverse hind limb paresis or paralysis that occurred between 2 and 18 days after dosing. Those findings were rare and resulted in a poor general condition requiring euthanasia.

Save Your Maximum Tolerated Dose: How to Diagnose Procedure-Related Spinal Cord Lesions After Lumbar Intrathecal Bolus Administration of Oligonucleotides in Cynomolgus Monkeys.

Many potential drugs for treatment of neurodegenerative diseases, particularly antisense oligonucleotides (ASOs), are administered via lumbar intrathecal injection, because these drugs do not cross the blood-brain barrier. Intrathecal injection is a well-established method in cynomolgus monkeys, a species that is used in preclinical safety assessment when other nonrodent species cannot be used. The authors completed intrathecal ASO administration in over 30 preclinical safety studies (>1000 animals and >4500 dose administrations) during which we observed 3 cases of procedure-related spinal cord necrosis (incidence <0.1%). We describe clinical symptoms, diagnostic approaches, morphological features, and prognosis of this rare injury, and compare these findings with typical drug-related findings of ASOs dosed by intrathecal injection. The low incidence of procedure-related and dose-limiting lesions confines this analysis to a small sample set. The pattern of effects is similar across all monkeys despite differences in age, body weight, and intrathecal injection site. All 3 cases presented a combination of the following findings: blood in cerebrospinal fluid at time of injection, clinical signs that increase in severity within a day of dosing, lameness of both hind limbs, reduced muscle tone, and loss of patellar, foot grip, and/or anal reflexes. In all cases, magnetic resonance imaging (MRI) showed a linear hyperintense lesion in the lumbar spinal cord. In 2 cases, this hyperintensity was associated with evidence of spinal cord edema. We conclude that a pattern of in-life and pathology findings, including noninvasive MRI assessment, is indicative of procedure-related effects.

Toxicologic Pathology Forum*: Opinion on Sexual Maturity and Fertility Assessment in Long-tailed Macaques ( Macaca fascicularis) in Nonclinical Safety Studies.

If nonhuman primates represent the only relevant species for nonclinical safety evaluation of biotechnology-derived products, male and female fertility effects can be assessed in repeat dose toxicity studies given that sexually mature monkeys are used. This opinion piece provides recommendations for determining sexual maturity and when/how fertility assessments should be conducted in the cynomolgus monkey. Male sexual maturity should be proven by presence of sperm in a semen sample, female sexual maturity by at least two consecutive menstrual bleedings. As per regulatory guidance, default parameters for an indirect assessment of fertility in both sexes are reproductive organ weight and histopathology. Beyond default parameters, daily vaginal swabs are recommended for females, and for males, it is recommended to include blood collections (for potential analysis of reproductive hormones), testis volume sonography, and collection of frozen testis samples at necropsy. Only if there is a cause for concern, blood collection for potential reproductive hormone analysis should be conducted in females and semen analysis in males. In principle, adverse reproductive effects can be detected within 4 weeks of test article administration, depending on study design and reproductive end point chosen. Therefore, there are options for addressing reproductive toxicity aspects with studies of less than 3 months dosing duration. *This is an opinion article submitted to the Toxicologic Pathology Forum. It represents the views of the authors. It does not constitute an official position of the Society of Toxicologic Pathology, British Society of Toxicological Pathology, or European Society of Toxicologic Pathology, and the views expressed might not reflect the best practices recommended by these Societies. This article should not be construed to represent the policies, positions, or opinions of their respective organizations, employers, or regulatory agencies.

A Brief Introduction to Antibody-Drug Conjugates for Toxicologic Pathologists.

Antibody-drug conjugates (ADCs) are an emerging class of anticancer therapeutics, delivering highly cytotoxic molecules directly to cancer cells. ADCs are composed of an antibody, a small molecule drug, and a linker attaching one to another. Antibodies are directed to a large variety of antigens overexpressed on tumor cells, tumor vasculature, or tumor-supporting stroma. After internalization, the ADC is transferred to lysosomes where the cytotoxic component is released, finally killing the target cell. All ADCs are administered via intravenous injection. Once in the circulation, linker stability in plasma is of high importance. In vivo studies in animals address the release of payload over time and typically measure total antibody, conjugated ADC, and free drug. ADC development is driven by ICH (International Council for Harmonisation) guidelines S6(R1) and S9. Dose-limiting toxicities of current ADCs are mainly associated with the payload and correlate well between clinical trials and nonclinical studies in rodents and nonrodents. This mini review is intended to provide general information about ADCs in oncology and shall assist the toxicologic pathologist in correctly interpreting morphological findings acquired in toxicity studies with this entity.

Recommended Diagnostic Approach to Documenting and Reporting Skin Findings of Nonhuman Primates from Regulatory Toxicity Studies.

Cutaneous adverse drug reactions (CADRs) in patients are not uncommon, and they are difficult to predict from nonclinical safety studies. Nonhuman primates (NHPs) are predestinated for a high predictivity of adverse drug reactions, and we postulate that this may also be true for CADRs, if skin findings in NHPs are thoroughly worked up, following the diagnostic approach in clinical veterinary dermatology. This article proposes a systematic approach to describe, analyze, and report skin findings that occur in NHP toxicity studies. Implementing this approach may increase the likelihood to differentiate between test item-related cutaneous findings and those that are independent of the test item. This will eventually result in increased relevance of skin findings identified in the scope of an NHP regulatory toxicity study for the risk assessment process to safeguard patients in clinical trials and beyond.

Acute effects of the glucagon-like peptide 2 analogue, teduglutide, on intestinal adaptation in short bowel syndrome.

Neonatal short bowel syndrome following massive gut resection is associated with malabsorption of nutrients. The intestinotrophic factor glucagon-like peptide 2 (GLP-2) improves gut function in adult patients with short bowel syndrome, but its effect in pediatric patients remains unknown. Our objective was to test the efficacy of the long-acting synthetic human GLP-2 analogue, teduglutide (ALX-0600), in a neonatal piglet jejunostomy model. Two-day-old pigs were subjected to resection of 50% of the small intestine (distal part), and the remnant intestine was exteriorized on the abdominal wall as a jejunostomy. All pigs were given total parenteral nutrition for 7 days and a single daily injection of the following doses of teduglutide: 0.01 (n = 6), 0.02 (n = 6), 0.1 (n = 5), or 0.2 mg · kg · day (n = 6), and compared with placebo (n = 9). Body weight increment was similar for all 4 teduglutide groups but higher than placebo (P < 0.05). There was a dose-dependent increase in weight per length of the remnant intestine (P < 0.01) and fractional protein synthesis rate in the intestine was increased in the 0.2 mg · kg · day group versus placebo (P < 0.001); however, functional and structural endpoints including activity of digestive enzymes, absorption of enteral nutrients, and immunohistochemistry (Ki67, villin, FABP2, ChgA, and GLP-2R) were not affected by the treatment. Teduglutide induces trophicity on the remnant intestine but has limited acute effects on functional endpoints. Significant effects of teduglutide on gut function may require a longer adaptation period and/or a more frequent administration of the peptide. In perspective, GLP-2 or its analogues may be relevant to improve intestinal adaptation in pediatric patients with short bowel syndrome.

Selective inhibition of PDE4 in Wistar rats can lead to dilatation in testis, efferent ducts, and epididymis and subsequent formation of sperm granulomas.

Testicular tubular dilatation and degeneration and epididymal sperm granulomas were frequently seen in 4-week toxicity studies using different phosphodiesterase-4 (PDE4) inhibitors in Wistar rats, including the prototypic PDE4 inhibitor BYK169171. To investigate the pathogenesis of testicular and epididymal lesions, a time course study with BYK169171 was conducted with sequential necropsies after 7, 14, 21, and 28 days of treatment. After 7 days, a dilatation of efferent ducts and of the initial segment of the epididymis and a subacute interstitial inflammation were seen followed by a diffuse dilatation of seminiferous tubules in the testis. Dilatation and inflammation were most pronounced after 14 days. Single animals also exhibited vascular necrosis in the inflamed interstitium. Although dilatation decreased later in the study, the incidence and severity of tubular degeneration increased from 14 days onward. Sperm granulomas developed in efferent ducts and in the caput and cauda of the epididymis after 14 days. Our results demonstrate a clear time course of PDE4 inhibition-induced lesions, with dilatation preceding sperm granuloma formation. We conclude that the most likely mechanism of toxicity is a disturbance of fluid homeostasis in efferent and epididymal ducts resulting in abnormal luminal fluid and sperm contents, epithelial damage at specific sites of the excurrent duct system, sperm leakage, and granuloma formation.

Proliferative and non-proliferative lesions of the rat and mouse soft tissue, skeletal muscle and mesothelium.

The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying lesions observed in the soft tissues including skeletal muscle as well as the mesothelium of rats and mice. The standardized nomenclature of lesions presented in this document is also available electronically on the Internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous developmental and aging lesions as well as those induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for lesions in soft tissues, skeletal muscle and mesothelium in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists. (DOI: 10.1293/tox.26.1S; J Toxicol Pathol 2013; 26: 1S-26S).

Proliferative and non-proliferative lesions of the rat and mouse integument.

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) project is a joint initiative of the societies of toxicological pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP). Its aim is to develop an internationally-accepted nomenclature for proliferative and non-proliferative lesions in laboratory rodents. A widely accepted international harmonization of nomenclature in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and will provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists. The purpose of this publication is to provide a standardized nomenclature for classifying microscopical lesions observed in the integument of laboratory rats and mice. Example colour images are provided for most lesions. The standardized nomenclature presented in this document and additional colour images are also available electronically at http://www.goreni.org. The nomenclature presented herein is based on histopathology databases from government, academia, and industrial laboratories throughout the world, and covers lesions that develop spontaneously as well as those induced by exposure to various test materials. (DOI: 10.1293/tox.26.27S; J Toxicol Pathol 2013; 26: 27S-57S).

How important are concurrent vehicle control groups in (sub)chronic non-human primate toxicity studies conducted in pharmaceutical development? An opportunity to reduce animal numbers.

Safety assessment of human pharmaceuticals demands extensive animal experiments before a compound can be tested in patients or released on the market. Such experiments typically include concurrent vehicle control groups. Reconsidering the need for concurrent controls could support the strive to reduce the use of animals for scientific purposes. We reviewed reports from 20 (sub)chronic toxicity studies that were conducted in non-human primates (NHP) to characterize hazards of novel human pharmaceuticals. Firstly, we determined the toxicological endpoints that were identified to characterize the hazard. Secondly, we evaluated if the hazard could have been identified without reference to the concurrent controls. Thirdly, we employed an alternative statistical method to test for any significant change related to dose level or time. We found that toxicologically relevant hazards were identifiable without reference to concurrent controls, because individual measurements could be compared with pre-dosing values or because individual measurements could be compared to historical reference data. Effects that could not be evaluated without reference to concurrent controls were clinical observations and organ weights for which appropriate historical reference data was not available, or immune responses that could not be compared to pre-dosing measurements because their magnitude would change over time. Our investigation indicates that concurrent control groups in (sub)chronic NHP toxicity studies are of limited relevance for reaching the study objective. Under certain conditions, regulatory (sub)chronic NHP toxicity studies represent a good starting point to implement virtual control groups rather than concurrent control groups in nonclinical safety testing.

Five cases of pigmented paravenous retinochoroidal atrophy in dogs.

OBJECTIVE: To describe a funduscopic finding in dogs that is referred to as Pigmented Paravenous Retinochoroidal Atrophy (PPRCA). ANIMALS STUDIED: Over a period of 24 years of ophthalmological practice, five cases of a characteristic paravenous retinal atrophy were observed in dogs. PROCEDURES: A comprehensive clinical ophthalmological examination in all five dogs was complemented by abdominal sonography (cases 1, 3), clinical pathology analysis (cases 1, 3, 4), and a histological examination of both bulbi, kidneys, spleen, and liver in one dog (case 1). RESULTS: Localized hyper-reflectivity in the tapetal fundus was observed in all five dogs and demonstrated a characteristic perivascular distribution along some peripheral retinal blood vessels. In these areas, geographic copper-brown coloration that tended to become darker with time was seen. Ophthalmoscopic signs of inflammation were lacking. The funduscopic abnormalities slowly progressed in size over years. Visual impairment could not be detected. Histopathology in one dog revealed severe retinal atrophy with multifocal perivascular distribution, mainly affecting the tapetal fundus and occasionally expanding into the nontapetal fundus. CONCLUSIONS: The described retinal lesions bear similarities with PPRCA in humans. As in humans, it appears to be an incidental funduscopic finding that is not associated with obvious vision impairment.

Safe and Effective Cynomolgus Monkey GLP-Tox Study with Repetitive Intrathecal Application of a TGFBR2 Targeting LNA-Gapmer Antisense Oligonucleotide as Treatment Candidate for Neurodegenerative Disorders.

The capability of the adult central nervous system to self-repair/regenerate was demonstrated repeatedly throughout the last decades but remains in debate. Reduced neurogenic niche activity paralleled by a profound neuronal loss represents fundamental hallmarks in the disease course of neurodegenerative disorders. We and others have demonstrated the endogenous TGFß system to represent a potential pathogenic participant in disease progression, of amyotrophic lateral sclerosis (ALS) in particular, by generating and promoting a disequilibrium of neurodegenerative and neuroregenerative processes. The novel human/primate specific LNA Gapmer Antisense Oligonucleotide "NVP-13", targeting TGFBR2, effectively reduced its expression and lowered TGFß signal transduction in vitro and in vivo, paralleled by boosting neurogenic niche activity in human neuronal progenitor cells and nonhuman primate central nervous system. Here, we investigated NVP-13 in vivo pharmacology, safety, and tolerability following repeated intrathecal injections in nonhuman primate cynomolgus monkeys for 13 weeks in a GLP-toxicology study approach. NVP-13 was administered intrathecally with 1, 2, or 4 mg NVP-13/animal within 3 months on days 1, 15, 29, 43, 57, 71, and 85 in the initial 13 weeks. We were able to demonstrate an excellent local and systemic tolerability, and no adverse events in physiological, hematological, clinical chemistry, and microscopic findings in female and male Cynomolgus Monkeys. Under the conditions of this study, the no observed adverse effect level (NOAEL) is at least 4 mg/animal NVP-13.

Reconditioning the Neurogenic Niche of Adult Non-human Primates by Antisense Oligonucleotide-Mediated Attenuation of TGFß Signaling.

Adult neurogenesis is a target for brain rejuvenation as well as regeneration in aging and disease. Numerous approaches showed efficacy to elevate neurogenesis in rodents, yet translation into therapies has not been achieved. Here, we introduce a novel human TGFß-RII (Transforming Growth Factor-Receptor Type II) specific LNA-antisense oligonucleotide ("locked nucleotide acid"-"NVP-13"), which reduces TGFß-RII expression and downstream receptor signaling in human neuronal precursor cells (ReNcell CX® cells) in vitro. After we injected cynomolgus non-human primates repeatedly i.th. with NVP-13 in a preclinical regulatory 13-week GLP-toxicity program, we could specifically downregulate TGFß-RII mRNA and protein in vivo. Subsequently, we observed a dose-dependent upregulation of the neurogenic niche activity within the hippocampus and subventricular zone: human neural progenitor cells showed significantly (up to threefold over control) enhanced differentiation and cell numbers. NVP-13 treatment modulated canonical and non-canonical TGFß pathways, such as MAPK and PI3K, as well as key transcription factors and epigenetic factors involved in stem cell maintenance, such as MEF2A and pFoxO3. The latter are also dysregulated in clinical neurodegeneration, such as amyotrophic lateral sclerosis. Here, we provide for the first time in vitro and in vivo evidence for a novel translatable approach to treat neurodegenerative disorders by modulating neurogenesis.

A multicentre placebo-controlled clinical trial on the efficacy of oral ciclosporin A in the treatment of canine idiopathic sebaceous adenitis in comparison with conventional topical treatment.

Canine idiopathic sebaceous adenitis (ISA) is an inflammatory reaction of sebaceous glands, potentially resulting in their complete loss. It is considered a T-cell-mediated disease, but its precise pathogenesis is still unknown. Topical treatment with oil soaks, humectants and shampoos is effective but laborious. Ciclosporin A (CsA), an immunomodulatory drug, has recently been shown to ameliorate the clinical picture of ISA and to reduce inflammation greatly. It is, however, an expensive treatment option. The objective of this multicentre, partly double-blinded, randomized controlled study was to evaluate the efficacy of ciclosporin A, either alone or with topical therapy, in comparison to conventional topical treatment alone, as measured by the primary end-points alopecia and scaling, and multiple histopathological secondary objectives. Thirty-four dogs with an established diagnosis were treated for 4-6 months and were evaluated before, during and after therapy. Both CsA and topical therapy demonstrated efficacy in this study. Differences between the treatment protocols were marginal. Topical treatment, both alone and in combination with CsA, appeared to reduce scaling more effectively than CsA alone. Both therapies reduced alopecia. There is evidence of a synergistic benefit on both scaling and alopecia, if both treatment options are combined. Inflammation of the sebaceous glands is also best reduced by a combination of both CsA and topical therapy. There is evidence that regeneration of sebaceous glands is best achieved by CsA, either given alone or in combination with topical treatment.

Research Relevant Conditions and Pathology in Nonhuman Primates.

Biomedical research involving animal models continues to provide important insights into disease pathogenesis and treatment of diseases that impact human health. In particular, nonhuman primates (NHPs) have been used extensively in translational research due to their phylogenetic proximity to humans and similarities to disease pathogenesis and treatment responses as assessed in clinical trials. Microscopic changes in tissues remain a significant endpoint in studies involving these models. Spontaneous, expected (ie, incidental or background) histopathologic changes are commonly encountered and influenced by species, genetic variations, age, and geographical origin of animals, including exposure to infectious or parasitic agents. Often, the background findings confound study-related changes, because numbers of NHPs used in research are limited by animal welfare and other considerations. Moreover, background findings in NHPs can be exacerbated by experimental conditions such as treatment with xenobiotics (eg, infectious morphological changes related to immunosuppressive therapy). This review and summary of research-relevant conditions and pathology in rhesus and cynomolgus macaques, baboons, African green monkeys, common marmosets, tamarins, and squirrel and owl monkeys aims to improve the interpretation and validity of NHP studies.