Development of a macromolecular prodrug of FK 506: III: In vivo disposition of FK 506-dextran conjugate.
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Biomedical subjects
Publications and source records attributed to N Yoshimura.
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The storage and periodic elimination of urine are dependent upon neural circuits in the brain and spinal cord that co-ordinate the activity of the urinary bladder, the urethra and the striated urethral sphincter. This study utilized anatomical, electrophysiological and pharmacological techniques to examine: (1) the organization of the parasympathetic excitatory reflex mechanisms that control the urinary bladder of the rat and the cat; and (2) the changes in these reflexes during postnatal development and after spinal cord injury. In normal adult cats and rats, the parasympathetic excitatory input to the bladder is dependent upon a spinobulbospinal reflex pathway that is activated by myelinated (Adelta) bladder afferents and that passes through an integrative center (the pontine micturition center, PMC) in the rostral brain stem. Transneuronal tracing studies using pseudorabies virus as well as physiological methods have revealed that the PMC is located in close proximity to the locus coeruleus. Single unit recordings indicate that neurons in the PMC respond to afferent input from the bladder and are excited prior to or during reflex bladder contractions. Glutamic acid is the major excitatory transmitter in the micturition reflex pathway. Glutamatergic transmission which is mediated by AMPA/kainate and NMDA receptors can be modulated by a variety of other transmitters. In neonatal animals, a spinal micturition reflex is activated by somatic afferent fibers from the perigenital region. This reflex is suppressed during postnatal development, but can be unmasked in adult animals following spinal cord injury. Spinal injury also causes the emergence of a spinal bladder-to-bladder reflex which in the cat is activated by capsaicin-sensitive C-fiber bladder afferents. Patch clamp studies in spinal cord slice preparations indicate that developmental and spinal cord injury induced plasticity in sacral parasympathetic reflex pathways is due in part to alterations in glutamatergic excitatory transmission between interneurons and preganglionic neurons. Changes in the electrical properties of bladder afferent pathways may also contribute to the reorganization of bladder reflexes in paraplegic animals.
The effect of chronic spinal cord transection on neurofilament immunoreactivity and capsaicin sensitivity of L6 and S1 dorsal root ganglion neurons innervating the urinary bladder was examined using an antibody (RT97) against 200,000 mol. wt subunit of neurofilament protein and a cobalt uptake assay, respectively. Bladder afferent neurons labelled by axonal transport of a fluorescent dye (Fast Blue) injected into the bladder wall were identified in sections of intact dorsal root ganglia and among dissociated neurons in short-term culture. Approximately two thirds of bladder afferent neurons from spinal intact rats were neurofilament-poor (i.e. C-fibre neurons). These neurons were on average 37% smaller in cross-sectional area than neurofilament-rich neurons (A delta-fibre neurons). In spinal intact rats, 78% of neurofilament-poor dissociated bladder afferent neurons were sensitive to capsaicin, while only 6.2% of neurofilament-rich neurons were capsaicin-sensitive. Dissociated bladder afferent neurons from spinal transected animals had larger diameters (34.2 +/- 1.1 microns) than those from spinal intact animals (29.2 +/- 1.2 microns). In tissue sections from dorsal root ganglia, the mean cross-sectional area of bladder afferent neuron profiles in spinal transected animals was also larger by approximately 35% than in spinal intact animals. Immunoreactivity to neurofilament protein which occurred in 32% of bladder afferent neurons in spinal intact animals was detected in a larger percentage (56% to 62%) of neurons from spinal transected animals. Conversely, the population of capsaicin-sensitive dissociated neurons was reduced from 55% in spinal intact rats to 38% in spinal transected rats. These results indicate that spinal cord injury induces functional and morphological plasticity in C-fibre visceral afferent neurons innervating the urinary bladder.
Hip fracture incidence is lower in Japan than in the West. Although differences have been found in peak bone mass and hip geometry between white and Japanese populations, these do not fully explain the difference in hip fracture rates. Variation in the rates of involutional bone loss may be an additional contributing factor. We address this issue in a prospective epidemiological study comparing bone loss rate among elderly people in Britain and Japan. Two population-based studies of bone loss rate in a British and a Japanese cohort were performed. Annual bone loss rates were obtained for 172 Hertfordshire men and 143 Hertfordshire women of mean age 66 years, and a questionnaire administered to obtain information on known confounding lifestyle factors. Eighty-six Japanese men and 90 Japanese women of mean age 69 years completed a similar study in Taiji, Japan. British men and women were heavier than Japanese men and women. Differences in lifestyle were also evident; the British men were less likely to smoke and the women more likely to consume alcohol than their Japanese counterparts. The British population also spent more time walking outdoors. Statistically significant differences between the two populations were apparent in baseline bone mineral density at lumbar spine (p < 0.05) and trochanter (p < 0.001) in men and women with Japanese subjects having lower values. There were also significant differences in bone density at the femoral neck (p < 0.001) between British and Japanese males. Men gained bone at the lumbar spine over the follow-up period in both populations. Bone loss rates were generally greater in the British female population than in Japanese women: the difference was statistically significant at the femoral neck (p < 0.05) and femoral trochanter (p < 0.001). These differences all remained significant after adjustment for differences in age between the two populations. Japanese subjects appear to have lower peak bone mass, but slower bone loss rates in later life than their European counterparts. These differences in bone loss rate help to explain the relatively low hip fracture rates found in Japan.
OBJECTIVE: Geographic differences in the prevalence of hip osteoarthritis (OA) have been ascribed to differences in the frequency of acetabular dysplasia among different ethnic groups. However, there are few data on the shape of the acetabulum in various populations around the world. We examined this issue in samples of pelvic radiographs from Britain and Japan. METHODS: Measurements were made on the pelvic radiographs of 1303 men and 195 women, aged 60-75 yr, who attended for i.v. urography in two British centres. These were compared with 99 men and 99 women aged 60-79 yr who were included in a population-based study in a rural community in Japan, and who agreed to undergo standardized pelvic radiography. Acetabular dysplasia was assessed by morphometric measurement of the centre-edge (CE) angle and acetabular depth. RESULTS: The mean CE angle among men was 36 degrees (95% CI 35-37 degrees ) in Britain and 31 degrees (95% CI 29-32 degrees ) in Japan; that in women was 37 degrees (95%, CI 36-38 degrees ) in Britain and 31 degrees (95% CI 29 33 degrees ) in Japan. The mean values of acetabular depth were also significantly (P < 0.001) lower in Japan than in Britain. However, the prevalence of hip OA was lower in Japan (0% in men, 2% in women) than in Britain ( 11% in men, 4.8 / in women). In a random effects model, there were negative relationships between measures of acetabular dysplasia and minimum joint space among individuals. CONCLUSIONS: We conclude that there are marked differences in pelvic morphometry between Britain and Japan. The acetabular dimensions of Japanese subjects are considerably shallower than those of their British counterparts of similar age and sex. Nevertheless, hip OA is more frequent in Britain than in Japan. Further studies are required on the risk factors for hip OA in Oriental populations, in order that the aetiology of this disorder can be better understood.
A case is presented of metastatic tumor causing Jacod's syndrome: total ophthalmoplegia, blindness, and trigeminal neuralgia. Abnormal soft tissue invading the orbital apex, anterior clinoid process, and cavernous sinus was difficult to assess by CT and MRI, but dual-isotope SPECT including Tc-99m HMDP bone imaging and Tl-201 tumor imaging strongly suggested that the cause of this rare syndrome was a small metastatic tumor. Although the therapeutic effect was also difficult to assess by anatomic imaging alone, dual-isotope SPECT after radiation therapy showed a decline of tumor viability.