Targeting activation-induced cytidine deaminase prevents colon cancer development despite persistent colonic inflammation.

Inflammatory bowel disease (IBD) is an important etiologic factor in the development of colorectal cancer. However, the mechanism underlying carcinogenesis through chronic inflammation is still unknown. Activation-induced cytidine deaminase (AID) is induced by the inflammation and involved in various human carcinogenesis via its mutagenic activity. In the current study, we investigated whether the inflammation/AID axis plays an integral role in the development of colitis-associated cancers. Inflammation in the cecum was more severe than that in other colonic regions, and endogenous AID expression was enhanced most prominently in the inflamed cecal mucosa of interleukin (IL)-10(-/-) mice. Blockade of tumor necrosis factor (TNF)-α and IL-12 significantly suppressed AID expression. Although proinflammatory cytokine expression was comparable between IL-10(-/-)AID(+/+) and IL-10(-/-)AID(-/-) mice, sequencing analyses revealed a significantly lower incidence of somatic mutations in Trp53 gene in the colonic mucosa of IL-10(-/-)AID(-/-) than IL-10(-/-)AID(+/+) mice. Colon cancers spontaneously developed in the cecum in 6 of 22 (27.2%) IL-10(-/-)AID(+/+) mice. In contrast, none of the IL-10(-/-)AID(-/-) mice developed cancers except only one case of neoplasia in the distal colon. These findings suggest that the proinflammatory cytokine-induced aberrant production of AID links colonic inflammation to an enhanced genetic susceptibility to oncogenic mutagenesis. Targeting AID could be a novel strategy to prevent colitis-associated colon carcinogenesis irrespective of ongoing colonic inflammation.

Insufficiency fracture of the spine: a prospective analysis based on radiographic and scintigraphic diagnosis.

To investigate the clinical characteristics of insufficiency fracture of the spine, patients aged 65 years or older, who had been hospitalized for acute low back pain without either an acute traumatic event or a previous history of malignant disease, were examined by plain radiographs and technetium-99m methylene disphosphonate bone scanning. Fifteen patients were diagnosed as having a vertebral insufficiency fracture on the basis of: (a) radiographic oseteopenia of the vertebra; (b) positive bone scan images; and (c) no episode of newly identified malignant disease in a subsequent 1 year follow up. These patients were analysed with respect to age, gender, bone mineral density, the number and distribution of the affected vertebrae, the extent of vertebral deformity, and consistency between radiographic and bone scan findings. Vertebral insufficiency fractures exhibited: (a) strict female predominance; (b) concave deformity of the affected vertebra; (c) a wide range of the vertebral height ratios and fracture distribution; and (d) low consistency between the vertebral deformity assessed by the lateral radiograph and positive activity on bone scanning. These findings represent a unique clinical feature of vertebral insufficiency fracture, and also emphasize the difficulty of radiographic diagnosis, as well as the importance of a comprehensive diagnostic approach.

Mechanosensitive afferent units in the lumbar posterior longitudinal ligament.

STUDY DESIGN: The mechanosensitive afferent units in the lumbar posterior longitudinal ligament were investigated in an animal model using an electrophysiologic technique. OBJECTIVES: The objectives of this study were to identify the mechanosensitive receptive fields in the lumbar posterior longitudinal ligament and to investigate their distribution and characteristics. SUMMARY OF BACKGROUND DATA: The lumbar posterior longitudinal ligament has a nerve network originating from the sinuvertebral nerve. These fibers are thin, and most of their terminals are free nerve endings. Some immunohistochemical studies have indicated that they are immunoreactive to calcitonin gene-related peptide and/or substance P, suggesting a nociceptive function. Most of these studies investigated morphologic aspects, and there have been few studies employing electrophysiologic techniques to examine mechanosensitive units. METHODS: We used 13 adult cats. They were anesthetized and then laminectomy was performed. The L5 and L6 dorsal rootlets were draped over a recording electrode. To investigate the receptive fields in the posterior longitudinal ligament, afferent impulses were evoked by mechanical stimulation with a glass probe. When the receptive fields were located, they were stimulated electrically to obtain conduction velocity and were stimulated with a set of 17 nylon filaments to determine their mechanical thresholds. RESULTS: Thirteen units were identified in the lumbar posterior longitudinal ligament. The majority of the units were located around the intervertebral disc level of the posterior longitudinal ligament. The mean mechanical threshold was 47.04 +/- 15.25 g. According to the conduction velocities of the units, 12 units were classified into Group III (0.5-2.5 m/sec) and one unit into Group IV (2.5-20 m/sec). CONCLUSION: Mechanosensitive units classified into Group III or Group IV and with a high mechanical threshold (>7.0 g) were thought to act as nociceptive units. All units identified in this study satisfied these criteria. Our result suggests that afferent fibers from the lumbar posterior longitudinal ligament have a principally nociceptive function.

Mechanosensitive afferent units in the shoulder and adjacent tissues.

Electrophysiologic experiments were done to identify the somatosensory afferent units in the shoulder and adjacent tissues of the rabbit. Conduction velocity and mechanical threshold of the units were examined to determine whether the units have a nociceptive function or proprioceptive function. Eighty mechanosensitive units were identified in the shoulder and adjacent tissues. Forty-six of these units were found in the rotator cuff area, 26 in the supraspinatus muscle, and eight in the infraspinatus muscle. These tissues contained low to high threshold Group II and Group III units. This study showed there are nociceptors that receive pain sensation and proprioceptors that receive position sense with motion of the shoulder in the rotator cuff and the supraspinatus and infraspinatus muscles. The high density of nociceptors found in the rotator cuff and infraspinatus muscles near their insertion to the shoulder suggests these tissues are more sensitive to noxious stimuli.

Neural response of mechanoreceptors to acute inflammation in the rotator cuff of the shoulder joint in rabbits.

We examined with electrophysiological techniques the effects of experimentally induced inflammation on the mechanosensitive afferent units in the rotator cuff of the shoulder joint of 21 rabbits. We identified 21 mechanosensitive units belonging to group III. 12 units had mechanical thresholds of > 7.0 g and 9 units had thresholds of < 7.0 g. After injection of inflammatory agents, kaolin and carrageenan, into the joint space, ongoing afferent discharge rates increased in all units. The average discharge rate increased significantly from 7 imp/s to 15 imp/s after injection. 5 units had a decreased mechanical threshold after the injection. Acute inflammation seems to have an excitatory and sensitizing effect on the high- and low-threshold units in the rotator cuff.

Mechanosensitive afferent units in the lateral ligament of the ankle.

We have studied the mechanosensitive afferent units in the lateral ligament of the ankle of the cat, with reference to the causes of lateral instability after injury, using electrophysiological recording from the lumbar dorsal rootlets. We identified 30 mechanosensitive units in the lateral ligament; 28 (93%) were located near the attachment to the fibula and calcaneus, which included both low-threshold group-II units and low- and high-threshold group-III units. Our results indicate that there are both proprioceptors and nociceptors in the lateral ligament of the cat ankle, and confirm that afferent fibres from the lateral ligament may contribute to the stability of the joint by regulation of position and movement.

A morphological study of the fibrous capsule of the human lumbar facet joint.

STUDY DESIGN: Macroscopic and microscopic investigations of the human lumbar facet joint capsule were undertaken. OBJECTIVE: To describe the morphologic characteristics of the fibrous capsule of the lumbar facet joints. SUMMARY OF BACKGROUND DATA: Previous biomechanical and neurophysiologic studies by the authors have shown that the lumbar facet joint capsule may be a source of low back pain. METHODS: Macroscopic investigation was performed on the facet joint capsules dissected from five fresh adult cadavers. For microscopic studies, facet joint capsules obtained from cadaver dissection and spinal surgeries were stained by the hematoxylin and eosin method and the Elastica-Van Gieson method. RESULTS: The outer layer of the fibrous capsule is a dense regular connective tissue that is composed of parallel bundles of collagenous fibers. The inner layer of the fibrous capsule consists of bundles of elastic fibers, similar to the ligamentum flavum. In the superior and middle part of the joint, the fibers run in the medial to lateral direction, crossing over the joint gap. In the inferior part of the joint, the fibers are relatively long and run in a superior-medial to inferior-lateral direction, covering the inferior articular recess. They are thicker than the layer in the superior and middle parts of the joint. CONCLUSIONS: Anatomical and histologic features of the lumbar facet joint capsule are different between its outer layer and inner layer. This complex of morphologic factors can affect the biomechanics and neurophysiology of the lumbar facet joint.

Mechanosensitive afferent units in the lumbar intervertebral disc and adjacent muscle.

The purpose of this study was to characterize the somatosensory units of the lumbar intervertebral disc and adjacent muscle. A laminectomy was performed on the lumbar spine of adult male Japanese White rabbits. Receptive fields of mechanosensitive afferent units were investigated in the intervertebral disc and adjacent muscle, and electrophysiologic recordings were obtained from filaments of the dorsal root. Thirteen mechanosensitive units were identified: three units in the intervertebral disc area, and 10 units in the psoas muscle. Of the three units in the disc area, one was identified at the surface of the L5-6 anulus fibrosus and two at the insertion of the anulus fibrosus to the L5 and L6 vertebral bodies. These three units belonged to Group III and had very high mechanical thresholds, more than 160 g. The 10 units in the psoas muscle belonged to Groups II, III, and IV, and had mechanical thresholds ranging from 0.22 to 12.6 g. The units in the disc area may serve as nociceptors sensitive to strong noxious stimulation that could traumatize the tissue. The units in the psoas muscle may contribute to nociception and proprioception.

Determination of haloperidol in human serum by radioimmunoassay.

A radioimmunoassay has been developed which enables accurate determination of haloperidol in human serum. Antiserum was prepared by immunizing guinea pigs with haloperidol (O-carboxymethyl)oxime derivative (III) coupled with bovine serum albumin. With the antiserum, 3H-haloperidol and dextran-coated charcoal, the assay of haloperidol in serum was possible over a concentration range of 1 to 50 ng/ml, using 0.1 ml of human serum without the need of an extraction procedure. Data obtained by radioimmunoassay are in good agreement with those obtained by gas chromatography. No appreciable cross-reactivity was observed neither with haloperidol metabolites nor with other butyrophenone neuroleptics. Serum levels of haloperidol in schizophrenic patients receiving single oral dosing (6 mg/subject) have also been determined.