Patricia Bock

University of Veterinary Medicine Hannover, Hanover, Lower Saxony, Germany

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Publications (12)40.24 Total impact

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    ABSTRACT: Spinal cord injury (SCI) represents a devastating central nervous system disease that still lacks sufficient therapies. Here, dogs are increasingly recognized as a preclinical animal model for the development of future therapies. The aim of this study was a detailed characterization of axonopathy in canine intervertebral disc disease, which produces a mixed contusive and compressive injury and functions as a spontaneous translational animal model for human SCI. The results revealed an early occurrence of ultrastructurally distinct axonal swelling. Immunohistochemically, enhanced axonal expression of β-amyloid precursor protein, non-phosphorylated neurofilament (n-NF) and growth-associated protein-43 was detected in the epicenter during acute canine SCI. Indicative of a progressive axonopathy, these changes showed a cranial and caudally accentuated spatial progression in the subacute disease phase. In canine spinal cord slice cultures, immunoreactivity of axons was confined to n-NF. Real-time quantitative polymerase chain reaction of naturally traumatized tissue and slice cultures revealed a temporally distinct dysregulation of the matrix metalloproteinases (MMP)-2 and MMP-9 with a dominating expression of the latter. Contrasting to early axonopathy, diminished myelin basic protein immunoreactivity and phagocytosis were delayed. The results present a basis for assessing new therapies in the canine animal model for translational research that might allow partial extrapolation to human SCI.
    Brain Pathology 07/2012; · 4.74 Impact Factor
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    ABSTRACT: Neuronal ceroid lipofuscinosis (NCL) is a progressive neurodegenerative disease characterized by brain and retinal atrophy and the intracellular accumulation of autofluorescent lysosomal storage bodies resembling lipofuscin in neurons and other cells. Tibetan terriers show a late-onset lethal form of NCL manifesting first visible signs at 5-7 years of age. Genome-wide association analyses for 12 Tibetan-terrier-NCL-cases and 7 Tibetan-terrier controls using the 127K canine Affymetrix SNP chip and mixed model analysis mapped NCL to dog chromosome (CFA) 2 at 83.71-84.72 Mb. Multipoint linkage and association analyses in 376 Tibetan terriers confirmed this genomic region on CFA2. A mutation analysis for 14 positional candidate genes in two NCL-cases and one control revealed a strongly associated single nucleotide polymorphism (SNP) in the MAPK PM20/PM21 gene and a perfectly with NCL associated single base pair deletion (c.1620delG) within exon 16 of the ATP13A2 gene. The c.1620delG mutation in ATP13A2 causes skipping of exon 16 presumably due to a broken exonic splicing enhancer motif. As a result of this mutation, ATP13A2 lacks 69 amino acids. All known 24 NCL cases were homozygous for this deletion and all obligate 35 NCL-carriers were heterozygous. In a sample of 144 dogs from eleven other breeds, the c.1620delG mutation could not be found. Knowledge of the causative mutation for late-onset NCL in Tibetan terrier allows genetic testing of these dogs to avoid matings of carrier animals. ATP13A2 mutations have been described in familial Parkinson syndrome (PARK9). Tibetan terriers with these mutations provide a valuable model for a PARK9-linked disease and possibly for manganese toxicity in synucleinopathies.
    PLoS Genetics 10/2011; 7(10):e1002304. · 8.52 Impact Factor
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    ABSTRACT: Despite knowledge about the impact of brain inflammation on hippocampal neurogenesis, data on the influence of virus encephalitis on dentate granule cell neurogenesis are so far limited. Canine distemper is considered an interesting model of virus encephalitis, which can be associated with a chronic progressing disease course and can cause symptomatic seizures. To determine the impact of canine distemper virus (CDV) infection on hippocampal neurogenesis, we compared post-mortem tissue from dogs with infection with and without seizures, from epileptic dogs with non-viral aetiology and from dogs without central nervous system diseases. The majority of animals with infection and with epilepsy of non-viral aetiology exhibited neuronal progenitor numbers below the age average in controls. Virus infection with and without seizures significantly decreased the mean number of neuronal progenitor cells by 43% and 76% as compared to age-matched controls. Ki-67 labelling demonstrated that hippocampal cell proliferation was neither affected by infection nor by epilepsy of non-viral aetiology. Analysis of CDV infection in cells expressing caspase-3, doublecortin or Ki-67 indicated that infection of neuronal progenitor cells is extremely rare and suggests that infection might damage non-differentiated progenitor cells, hamper neuronal differentiation and promote glial differentiation. A high inter-individual variance in the number of lectin-reactive microglial cells was evident in dogs with distemper infection. Statistical analyses did not reveal a correlation between the number of lectin-reactive microglia cells and neuronal progenitor cells. Our data demonstrate that virus encephalitis with and without seizures can exert detrimental effects on hippocampal neurogenesis, which might contribute to long-term consequences of the disease. The lack of a significant impact of distemper virus on Ki-67-labelled cells indicates that the infection affected neuronal differentiation and survival of newborn cells rather than hippocampal cell proliferation.
    Neuropathology and Applied Neurobiology 08/2011; 38(5):426-42. · 4.84 Impact Factor
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    ABSTRACT: Better understanding of the pathogenesis of spinal cord injury (SCI) is needed for the development of new therapeutic strategies. Spinal cord injury has been investigated in various rodent models, but extrapolation to humans requires the use of a large animal model that more closely mimics human SCI. Dogs frequently develop spontaneous SCI with features that bear a striking resemblance to the human counterpart. We investigated the temporal course of the immune response during naturally occurring canine SCI and in organotypic canine spinal cord slice cultures that are devoid of peripheral immune cells. By immunohistochemistry, the inflammatory response in subacute canine SCI was largely restricted to resident immune cells as demonstrated by activation of major histocompatibility complex class II-expressing microglia/macrophages. By quantitative polymerase chain reaction, there was parallel upregulation of proinflammatory cytokine gene expression (i.e. of interleukin 6 [IL-6] and IL-8 with a trend toward upregulation of tumor necrosis factor) in acute canine SCI. Expression of neuroprotective cytokines (e.g. IL-10) remained unchanged, and transforming growth factor β upregulation was delayed. In organotypic spinal cord slices, there was similar activation of major histocompatibility complex class II-positive microglia and prolonged upregulation of inflammatory cytokines, indicating that resident rather than infiltrating cells play major roles in the postinjury immune response. Thus, canine SCI represents a bridge between rodent models and human SCI that may be relevant for clinical and preclinical treatment studies.
    Journal of Neuropathology and Experimental Neurology 08/2011; 70(8):703-14. · 4.35 Impact Factor
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    ABSTRACT: Olfactory ensheathing cells (OECs) are the non-myelinating glial cells of the olfactory nerves and bulb. The fragmentary characterization of OECs in situ during normal development may be due to their small size requiring intricate ultrastructural analysis and to the fact that available markers for in situ detection are either expressed only by OEC subpopulations or lost during development. In the present study, we searched for markers with stable expression in OECs and investigated the spatiotemporal distribution of CNPase, an early oligodendrocyte/Schwann cell marker, in comparison with the prototype marker p75(NTR). Anti-CNPase antibodies labeled canine but not rat OECs in situ, while Schwann cells and oligodendrocytes were positive in both species. CNPase immunoreactivity in the dog was confined to all OECs throughout the postnatal development and associated with the entire cell body, including its finest processes, while p75(NTR) was mainly detected in perineural cells and only in some neonatal OECs. Adult olfactory bulb slices displayed CNPase expression after 4 and 10 days, while p75(NTR) was detectable only after 10 days in vitro. Finally, treatment of purified adult canine OECs with fibroblast growth factor-2 significantly reduced CNPase expression at the protein and mRNA level. Taken together, we conclude that CNPase but not p75(NTR) is a stable marker suitable for in situ visualization of OECs that will facilitate their light-microscopic characterization and challenge our general view of OEC marker expression in situ. The fact that canine but not rat OECs expressed CNPase supports the idea that glia from large animals differs substantially from rodents.
    Cell and Tissue Research 06/2011; 344(3):391-405. · 3.68 Impact Factor
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    ABSTRACT: Spinal cord injury (SCI) in dogs is a well recognized animal model to study pathogenesis and treatment modalities of the debilitating human disease. To define the contributing role of microglial cell activation to the secondary wave following SCI, microglia from 15 dogs with SCI confirmed by imaging, gross, and histopathological examination were isolated and characterized in terms of morphology, immunophenotype, and function ex vivo by flow cytometry, allowing single cell analysis. The results were compared to region-specific findings obtained from healthy control dogs. Light microscopy revealed a significant enhancement of myelinophagia within the traumatized spinal cord of dogs who had had SCI for ≥5 days. Immunophenotypical characterization revealed increased expression of B7-1, B7-2, MHC II, CD1c, ICAM 1, CD14, CD44, and CD45 emphasizing the enhanced function of microglia as co-stimulators of T cells, in leukocyte adhesion and aggregation, and for lipid or glycolipid presentation. In addition, phagocytosis and reactive oxygen species (ROS) generation were significantly increased in dogs with spinal cord trauma. Regional differences within the spinal cord were observed by demonstrating disparities in microglial immunophenotypes in the traumatized cervical compared to the thoracolumbar spinal cord. In contrast to histopathology, microglia activation analyzed on a single cell basis did not depend upon the time span following SCI.
    Journal of neurotrauma 05/2011; 29(5):1000-11. · 4.25 Impact Factor
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    ABSTRACT: Incisional biopsies from the oral cavity of 2 adult cats were submitted for histological investigation. Cat No. 1 showed a solitary well-circumscribed neoplasm in the left mandible. Cat No. 2 demonstrated a diffusely infiltrating neoplasm in the left maxilla. Both tumors consisted of medium-size epithelial cells embedded in a fibrovascular stroma. The mitotic index was 0 to 1 mitosis per high-power field. The epithelial cells showed an irregular arrangement forming nests or streams in cat No. 1, whereas a palisading growth was noted in cat No. 2. Both tumors, especially that of cat No. 1, showed multifocal accumulations of amyloid as confirmed by Congo red staining and a distinct green birefringence under polarized light, which lacked cytokeratin immunoreactivity as well as and AL and AA amyloid immunoreactivity. In addition, the amyloid in cat No. 2 was positive for the odontogenic ameloblast-associated protein, formerly termed APin. In sum, both cats suffered from an amyloid-producing odontogenic tumor, but their tumors varied with respect to morphology and type of amyloid produced.
    Veterinary Pathology 02/2011; 48(4):906-10. · 1.93 Impact Factor
  • Journal of Comparative Pathology - J COMP PATHOL. 01/2010; 143(4):332-332.
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    ABSTRACT: The main olfactory epithelium is a pseudostratified columnar epithelium that displays neurogenesis over the course of a lifetime. New olfactory neurons arise basally and are transferred to the middle third of the epithelium during maturation. It is generally believed that this pattern is present throughout the olfactory area. In the present study, we show that the postnatal canine olfactory epithelium is composed of two distinct types of epithelium, designated A and B, which not only differ in olfactory neuron morphology, marker expression and basal cell proliferation but also display a patchy distribution and preferential localization within the nasal cavity. Type A epithelium, abundant in the caudal part of the olfactory area, contains well-differentiated olfactory neurons positive for olfactory marker protein but low numbers of immature neurons and proliferating basal cells, as visualized by TrkB/Human Natural Killer-1 (HNK-1) glyco-epitope and Ki-67 immunostaining, respectively. In contrast, type B epithelium is mainly found in the rostral part and contains smaller and elongated neurons that display increased levels of TrkB/Human Natural Killer-1 (HNK-1) glyco-epitope immunoreactivity and a higher number of Ki-67-positive basal cells but lower and variable levels of olfactory marker protein. The vomeronasal organ displays a uniform distribution of molecular markers and proliferating basal cells. The observation that olfactory marker protein in type A and B epithelium is preferentially localized to the nucleus and cytoplasm, respectively, implies correlation between subcellular localization and olfactory neuron maturation and may indicate distinct functional roles of olfactory marker protein. Whether the site-specific population dynamics in the postnatal canine olfactory epithelium revealed in the present study are modulated by physiological parameters, such as airflow, has to be clarified in future studies.
    Journal of Anatomy 09/2009; 215(5):522-35. · 2.36 Impact Factor
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    ABSTRACT: Presbyopia is an age related effect which affects every human at the age of about 40 years. So far reading glasses are the conventional treatment. According to Helmholtz' theory of accommodation one of the mayor reasons for the development of presbyopia is the increasing sclerosis of the lens. In contrast to that the ciliary muscle and the lens capsule remain mostly active and elastic the whole life. So a possible treatment could be the increase of the flexibility of the lens by creating gliding planes with fs-laser pulses inside the lens tissue. In former studies it was shown that fs-laser pulses were able to increase the flexibility of ex vivo porcine lenses as well as ex vivo human donor lenses. Our current aim was to evaluate the effect of the fs-laser pulses on the crystalline lens of living rabbit eyes due to the fs-lentotomy treatment. The main focus of the evaluation was the exclusion of possible side effects of the treatment like cataract formation or retina damage. The treated eyes were monitored using optical coherence tomography (OCT) and Scheimpflug imaging for localizing and studying the tissue effects of the incisions. Furthermore histological sections of the lens and retina were prepared. The rabbits were investigated pre operatively and up to six months post operatively. The fs-laser induced micro incisions were successfully applied to the left lens of each rabbit. The micro incisions within the crystalline lens were detectable with OCT and Scheimpflug imaging up to six month. The imaging within the lens showed a progressive fading of the incisional opacities generated by the femtosecond laser during the six months and no indication of cataract formation was found. OCT and Scheimpflug images emphasize themselves as necessary tools to monitor the micro incisions over time. Histopathological sections of the lens tissue support the findings of the non invasive imaging techniques. Also the histopathological sections of the retina show no thermal induced change due to the irradiation of the fs-pulses.
    Proceedings of the SPIE - The International Society for Optical Engineering; 01/2009
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    ABSTRACT: Olfactory ensheathing cells (OECs) are promising candidates for autologous cell transplantation therapies of nervous system injury and disease. Large animal models are relevant for transferring experimental data into clinical practice. In vivo studies have suggested that adult canine OECs may display similar regenerating capacities as their rodent counterpart. However, data on their molecular phenotype required for generating pure cell preparations are still scarce. In the present study, we comparatively analyzed expression of the carbohydrate HNK-1 epitope and the neurotrophin receptor p75NTR in adult canine Schwann cells and olfactory ensheathing cells in situ and in vitro. Myelinating and nonmyelinating Schwann cells in situ exclusively expressed HNK-1 and p75NTR, respectively, whereas OECs were negative for both markers. In vitro, OECs and Schwann cells shared cell surface expression of p75NTR but not of HNK-1, which could be detected transiently in intracellular vesicles. This suggests that Schwann cells and OECs in vitro phagozytose HNK-1+ cellular debris. The cultivation-induced downregulation of HNK-1 expression in Schwann cells and upregulation of p75NTR in OECs argues for the possibility that axonal signals control the expression of both markers in situ. Whereas HNK-1 expression in Schwann cells is most likely controlled by signals inducing myelination, e.g., neuregulin, the mechanisms that may suppress p75NTR expression in OECs in situ remain to be elucidated. Interestingly, HNK-1 expression in the adult dog was found in both sensory and motor nerve myelinating Schwann cells. This is reminiscent of humans and differs from rodents; it also underscores the importance of large animal models for translational research. J. Comp. Neurol. 505:572–585, 2007. © 2007 Wiley-Liss, Inc.
    The Journal of Comparative Neurology 12/2007; 505(5):572 - 585. · 3.66 Impact Factor
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    ABSTRACT: Growing rabbits from two rabbitries, fed with commercial concentrates and hay, developed painful thickenings of the extremities. Four rabbits from each farm were clinically examined and necropsied. All animals showed multiple moderate to severe osseous proliferations of extremities and mandibles and a mild to severe proliferative gastroduodenopathy. Histologically, periosteal and endosteal hyperostosis and a mild to severe proliferation of the gastric and duodenal mucosa were noted. Bone analyses revealed 12,700 and 15,000 microg fluoride per gram of bone ash in affected rabbits, compared with 550 microg fluoride in a control animal. A highly elevated fluoride content was found in concentrates. Vitamin A levels were moderately increased only in one concentrate, and copper levels were normal. Results indicate that alimentary fluoride intoxication caused prominent bony proliferations in the examined rabbits. Whether the proliferative gastroduodenopathy is related to the elevated fluoride intake or represents an incidentally occurring secondary disease remains to be determined.
    Veterinary Pathology 10/2007; 44(5):703-6. · 1.93 Impact Factor

Publication Stats

88 Citations
40.24 Total Impact Points

Institutions

  • 2007–2012
    • University of Veterinary Medicine Hannover
      • Institute of Pathology
      Hanover, Lower Saxony, Germany
    • Chulalongkorn University
      • Department of Pathology
      Bangkok, Bangkok, Thailand
    • American College of Pathologists
      American Fork, Utah, United States
  • 2011
    • Hannover Medical School
      • Institute for Functional and Applied Anatomy
      Hannover, Lower Saxony, Germany