L’endométriose est définie comme la présence de tissu endométrial et de stroma en dehors de la cavité utérine. Ses localisations les plus fréquentes sont le péritoine pelvien et les ovaires. L’endométriose infiltrante est classiquement décrite comme la présence de tissu endométriotique plus de cinq millimètres sous le péritoine pelvien ou la séreuse d’un organe. Histologiquement il s’agit d’une lésion endométriotique mais qui contrairement aux lésions ovariennes ou péritonéales contient significativement plus de muscle lisse et de fibrose et est davantage associée à la douleur. Les lésions infiltrantes peuvent être responsables de dysménorrhée, dyspareunie profonde et douleurs pelviennes chroniques sévères ayant un charactère hyperalgique tel qu’on peut le retrouver dans les douleurs neuropathiques. Ces douleurs nécessitent souvent la prise de quantités importantes d’antalgiques et ont des répercussions importantes sur la vie professionnelle, quotidienne et sexuelle des femmes atteintes. L’endométriose infiltrante présente un rapport histologique étroit avec les structures nerveuses du rétropéritoine ou les nerfs des organes atteints. Dans sa localisation rectovaginale il existe une relation histologique étroite entre les lésions d’endométriose et les nerfs ainsi qu’une correlation entre l’intensité de la douleur et le nombre de structures nerveuses envahies par l’endometriose ou engaînées dans la fibrose. Ces lésions infiltrantes expriment le «nerve growth factor» (NGF), une neurotrophine qui joue un rôle clé dans la genèse de l’hyperalgie et de la douleur. Les structures nerveuses du rétropéritoine pelvien expriment quant à elles le récepteur spécifique pour la neurotrophine NGF. Le système «NGF-récepteur spécifique» peut être responsable d’un chimiotactisme tissulaire entre les tissus sécrétant du NGF et les nerfs qui expriment le récepteur pour le NGF. Le système «NGF- récepteur spécifique» au sein de la relation endométriose-nerfs pourrait rendre compte du caractère hyperalgique des lésions endométriotiques infiltrantes ainsi, qu’expliquer pourquoi les lésions nodulaires n’apparaissent que dans les sites anatomiques richement innervés (ligaments utérosacrés, lame rectovaginale, paroi du rectum ou du côlon…) et pas ailleurs. Le traitement de première intention est chirurgical. Il convient d’être suffisamment agressif sur les lésions tout en engendrant le moins de séquelles postopératoires possibles sachant que nombre de ces femmes sont stériles. En cas d’atteinte digestive basse, les modalités de l’intervention sont dictées par l’extension et le degré d’infiltration de la paroi digestive. Dans le but de réaliser dans la majorité des cas une chirurgie minimalement invasive (laparoscopique) avec des cicatrices de petites tailles, nous avons développé une stratégie de traitement basée sur le degré d’infiltration de la paroi digestive. Dans ce cadre nous avons développé une technique laparo-assistée de résection colique segmentaire et de résection antérieure du rectum.

No description available.

Thesis. 1977. Ph.D.--Massachusetts Institute of Technology. Dept. of Electrical Engineering and Computer Science. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND ENGINEERING. / Vita. / Bibliography : leaves 175-184. / Ph.D.

Injuries to the peripheral nervous system rank among the most common causes of chronic neuropathic pain. Afflicting millions of people for months or even years, symptoms of this condition have proven difficult to treat clinically. A thorough understanding of the pathophysiological changes induced by such nerve lesions is essential to the development of more efficient therapeutic options. Peripheral nerve injury induces a robust and tightly regulated innate immune response in the dorsal horn of the spinal cord. The precise molecular mechanisms regulating the spatiotemporal dynamics and functional impact of the response remain incompletely understood. Preclinical evidence suggests mitigating this immune response can have a significant therapeutic benefit in the treatment of neuropathic pain, however these findings have yet to be clinically validated. To elucidate the mechanisms regulating the spinal immune response, we used a mouse model of partial sciatic nerve injury exclusively in male adult (2-3-month-old) mice. The spared nerve injury (SNI) model employed throughout our studies induces robust, persistent neuropathic pain-like behavior. We established a time course for the spinal immune response to SNI and used mRNA extracted from the ipsilateral dorsal horn of lumbar spinal cord segments L4 and L5 to analyze changes in the transcriptome at the peak of the immune reaction 7 days after nerve lesion. We discovered upregulation of multiple elements of the triggering receptor expressed on myeloid cells 2 (Trem2) pathway. Trem2 is considered a regulator of toll-like receptor signaling in innate immune cells. It also promotes microglia-mediated phagocytosis in the central nervous system. Recent work from our lab has established neuronal apoptosis in the ipsilateral dorsal horn after SNI as an essential mechanism leading to the development of chronic neuropathic pain-like behavior. We used TUNEL staining of L4 spinal cord sections to compare the clearance of apoptotic cell profiles in Trem2-/- mice to wild-type littermates and discovered a key role for Trem2 in the clearance of apoptotic cells after SNI. We further used genetic deletion of Trem2 as well as administration of a Trem2 agonist in C57Bl/6 mice to assess the impact of Trem2 signaling on both the spinal immune response and neuropathic pain-like behavior after SNI. Neither removal nor augmentation of Trem2 signaling significantly affected the development of neuropathic pain-like behavior. Utilizing flow cytometry, we also evaluated the cellular composition of the spinal immune response. We found no evidence that monocytes from the peripheral circulation invade the spinal cord after SNI, as has been previously suggested. These findings were corroborated by immunohistochemical analysis of spinal cord sections from transgenic mice that express distinct fluorescent proteins in their monocyte and microglia cell populations. To better understand the different mechanisms modulating the spinal immune response, we further examined several transcriptionally regulated signaling pathways. We achieved the greatest reduction of mechanical allodynia in nerve-lesioned mice treated with a P2x4r antagonist. Surprisingly, the removal of fractalkine (Cx3cl1) signaling, another prominent chemokine signaling pathway in microglia, had no significant impact on either the spinal immune response or mechanical allodynia after SNI. Reducing the number of spinal microglia by blocking Csf1r activation did not prevent the development of mechanical allodynia after SNI either. Our findings reveal a more nuanced concept of microglial activation after nerve injury. The impact on neuropathic pain-like behavior and phagocytosis appear to be regulated by pathways that differ from those controlling immune cell recruitment and global activation. These findings provide a greater understanding of the complex mechanisms governing microglial function and offer new insight into molecular targets essential to the development of more efficient treatment options for neuropathic pain.

INTRODUCTION: The cornea forms the anterior-most barrier of the eye, consisting of a non-keratinized pseudostratified squamous epithelium, a collagen-based stroma, and an endothelium. It is completely avascular, yet the most densely innervated structure in the human body. The sensory nerves project from the ophthalmic branch of the trigeminal cranial nerve into the limbal/stromal interface. From there, the nerves branch and ascend into Bowman’s membrane, a basal lamina delineating the epithelium from the stroma, and project into the epithelium as free nerve endings. Injury to the corneal epithelium can potentially lead to impaired vision if the wound healing process is not properly initiated. Immediately after injury, nucleotides such as ATP are released and bind to purinergic receptors known to be located in epithelial cell membranes, thereby initiating epithelial cell migration to close the wound. Malfunctions in the interactions between the corneal nerves and their epithelial counterparts during the wound healing process are thought to contribute to the attenuated wound healing characteristic of diabetes. However, the precise nature of these interactions, how they facilitate wound healing, and how they are impaired in diabetes, is not well understood. OBJECTIVES: Previously, our lab has shown that a member of purinergic family receptors (P2X7) is localized in the basal epithelial cells and becomes relocated to the leading edge of the wound after injury. When the relocation is inhibited, migration is attenuated. Additionally, it is known that diabetic mouse models display slower wound healing rates. The present study has three aims: (1) to replicate the characteristic sub-basal whorl organization of the corneal nerves in organ-cultured corneas; (2) to elucidate the connections between patterns of corneal innervation and purinergic receptor expression; and (3) to understand how these patterns interact to facilitate normal wound healing and how these interactions are disrupted in a diabetic model. METHODS: Our approach was to use immunohistochemistry of dissected mouse and to visualize the tissue using confocal microscopy. Sensory innervation profiles from diet induced obesity (DIO) mouse corneas and their wildtype C57Bl6 counterparts were compared in unwounded and wounded tissue. To image the nerves a methanol fixation protocol was optimized to examine the sub-basal plexus and the apical nerves. Corneas were dissected, stained with beta III-tubulin, which identifies nerves, and with an antibody to the P2X7 purinergic receptor, which is expressed in the epithelium and nerves. Trephine induced epithelial abrasion injuries were made on separate DIO and control models to compare re-epithelialization and re-innervation between the diseased and healthy states. Corneas were imaged using a Zeiss LSM 700 laser scanning confocal microscope and optical images were taken through the cornea over a distance averaging 115 microns. Corneas were imaged using a macro tiling plugin, stitching 3x3 optical z-stacks into composite images. The 3x3 tiles were created to image the central whorl, as well as the peripheral nerve fibers. Co-localization of P2X7 and betaIII tubulin were determined by thresholding using ImageJ/FIJI software. RESULTS: The elegant organization of the centralized sub-basal whorl of the control mouse was disrupted in the DIO mouse cornea, appearing fragmented and incomplete. Analysis of 7.5 and 15 wk corneas showed the whorl to be present at 7.5 wks. Average apical nerve fiber projection length was decreased in DIO cornea. Yet, analyses at each epithelial layer demonstrated overall increased apical nerve density in the DIO corneas as compared to control while sub-basal nerve density decreased dramatically. Stromal nerves remained equivalent. P2X7 did co-localize to the large stromal nerve fibers but it was difficult to show the localization along the sub-basal nerve plexus. However in cross-section images, P2X7 displayed an intracellular polarity, and was present along the apical surface of the columnar basal epithelial cells lining the basement membrane. This localization may suggest the presence of P2X7 expressing sensory nerves, which may be ideally poised for communication with the basal cells after injury. CONCLUSIONS: These data support the hypothesis that there is indeed a difference between diabetic and control corneal innervation. While wound healing differences due to the interaction between sensory nerves and the localization of P2X7 in epithelium at the leading edge remain to be fully elucidated, the novel finding of P2X7 expression in corneal nerves confirms a potential role of purinergic receptor and nerve coordination in conducting the wound healing response.

published_or_final_version / Orthopaedics and Traumatology / Master / Master of Medical Sciences

Not available / text

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

In standard anatomical textbooks, the formation of the cervical plexus is well defined; however the accurate differentiation into superficial and deep plexuses, their emerging patterns, and gross anatomical relations are not documented as expansively. In order to obtain detailed anatomical knowledge of the superficial and deep cervical plexuses, the investigation aimed to clarify the anatomy and variations of these plexuses, define possible anatomical landmarks, and record the relationship of the external jugular vein and muscles of the posterior triangle of neck to the branches of the superficial cervical plexus, and the relationship of the common carotid artery, internal jugular vein, sympathetic chain, cervical verterbrae, and vertebral artery to the deep cervical plexus. The studies utilized the gross anatomical dissection, morphological and statistical analyses of forty fetal and fifteen adult cadaveric, formalinized specimens. The branches of the superficial cervical plexus emerged from the posterior border of the sternocleidomastoid muscle at the great auricular point (situated in the middle third of the muscle) and was described as ascending (lesser occipital, great auricular, transverse cervical nerves) and descending (supraclavicular nerves). Further, these branches were recorded according to their branching patterns, relations to the external jugular vein and variations. The branching patterns are described as single, duplicate and triplicate. The external jugular vein was constantly located inferior to the great auricular nerve, superior to the transverse cervical nerve and intertwined with the branches of the supraclavicular nerves. Variations of the branches of the superficial cervical plexus were observed only in fetuses and classified according to their course, branching patterns and communications. The emerging point of the branches of the superficial cervical plexus on the sternocleidomastoid muscle, were determined according to the seven types of “emerging pattern” classification by Kim et al., (2002). In order to record the deep cervical plexus, the sternocleidomastoid muscle was reflected with the following observation: the ventral rami of the second and third cervical nerves emerged between the scalenus anterior and scalenus medius muscles, and the third and fourth cervical nerves was located at the lateral edge of scalenus medius muscle. The deep cervical plexus was described as communicating, muscular, ansa cervicalis, and phrenic nerves. The superior cervical ganglion constantly communicated with the ventral rami of the cervical nerves; and the hypoglossal communicated with the superior root of the ansa cervicalis. The muscular branches were observed to the scalenus anterior and scalenus medius muscles with an anomalous branch to the sternocleidomastoid muscle. The ansa cervicalis demonstrated a degree of variation with regard to its origin, course and formation of the loops. The phrenic nerve arose from the ventral rami of the third, fourth and fifth cervical nerves and descended on the lateral border of the scalenus anterior muscle. The precise understanding of the anatomy of the superficial and deep cervical plexuses together with variations may assist anesthetists and surgeons to accurately identify the vascular, neural and muscular structures and reduce the risks of complications when performing neural blocks in regional anesthesia, facial rejuvenation surgery and parotidectomies. / Thesis (M.Med.Sc.)-University of KwaZulu-Natal, Westville, 2010.