(18)F-FDG accumulation in atherosclerotic plaques: immunohistochemical and PET imaging study.

The rupture of atherosclerotic plaques and the subsequent formation of thrombi are the main factors responsible for myocardial and cerebral infarctions. Thus, the detection of vulnerable plaques in atherosclerotic lesions is a desirable goal, and attempts to image these plaques with (18)F-FDG have been made. In the present study, the relationship between the accumulation of (18)F-FDG and the biologic characteristics of atherosclerotic lesions was investigated. Furthermore, PET imaging of vulnerable plaques was performed with an animal model of atherosclerosis, Watanabe heritable hyperlipidemic (WHHL) rabbits. METHODS: WHHL (n = 11) and control (n = 3) rabbits were injected intravenously with (18)F-FDG, and the thoracic and abdominal aortas were removed 4 h after injection. The accumulated radioactivity was measured, and the number of macrophages and the intimal area were investigated by examination of stained sections. PET and CT images were also acquired at 210 min after injection of the radiotracer. RESULTS: (18)F-FDG accumulated to a significantly higher level in the aortas of the WHHL rabbits (mean +/- SD differential uptake ratio [DUR], 1.47 +/- 0.90) than in those of the control rabbits (DUR, 0.44 +/- 0.15); DUR was calculated as (tissue activity/tissue weight)/(injected radiotracer activity/animal body weight), with activities given in becquerels and weights given in kilograms. (18)F-FDG uptake and the number of macrophages were strongly correlated in the atherosclerotic lesions of the WHHL rabbits (R = 0.81). In the PET analysis, intense (18)F-FDG radioactivity was detected in the aortas of the WHHL rabbits, whereas little radioactivity was seen in the control rabbits. CONCLUSION: The results suggest that macrophages are responsible for the accumulation of (18)F-FDG in atherosclerotic lesions. Because vulnerable plaques are rich in macrophages, (18)F-FDG imaging should be useful for the selective detection of such plaques.     

Mechanisms for the enhancement of fracture healing in rats treated with intermittent low-dose human parathyroid hormone (1-34).

Recent reports have demonstrated that intermittent treatment with parathyroid hormone (1-34) [PTH(1-34)] increases callus formation and mechanical strength in experimental fracture healing. However, little is known about the optimal dose required for enhancement of fracture repair or the molecular mechanisms by which PTH regulates the healing process. In this study, we analyzed the underlying molecular mechanisms by which PTH affects fracture healing and tested the hypothesis that intermittent low-dose treatment with human PTH(1-34) can increase callus formation and mechanical strength. Unilateral femoral fractures were produced and a daily subcutaneous injection of 10 microg/kg of PTH(1-34) was administered during the entire healing period. Control animals were injected with vehicle solution alone. The results showed that on day 28 and day 42 after fracture, bone mineral content (BMC), bone mineral density (BMD), and ultimate load to failure of the calluses were significantly increased in the PTH-treated group compared with controls (day 28, 61, 46, and 32%; day 42, 119, 74, and 55%, respectively). The number of proliferating cell nuclear antigen (PCNA)-positive subperiosteal osteoprogenitor cells was significantly increased in the calluses of the PTH-treated group on day 2, and TRAP+ multinucleated cells were significantly increased in areas of callus cancellous bone on day 7. The levels of expression of type I collagen (COLlA1), osteonectin (ON), ALP, and osteocalcin (OC) mRNA were increased markedly in the PTH-treated group and accompanied by enhanced expression of insulin-like growth factor (IGF)-I mRNA during the early stages of healing (days 4-7). The increased expression of COL1A1, ON, ALP, and OC mRNA continued during the later stages of healing (days 14-21) despite a lack of up-regulation of IGF-I mRNA. These results suggest that treatment of fractures with intermittent low dose PTH(1-34) enhances callus formation by the early stimulation of proliferation and differentiation of osteoprogenitor cells, increases production of bone matrix proteins, and enhances osteoclastogenesis during the phase of callus remodeling. The resultant effect to increase callus mechanical strength supports the concept that clinical investigations on the ability of injectable low-dose PTH(1-34) to enhance fracture healing are indicated.     

Familial amyloid polyneuropathy in Taiwan: Identification of transthyretin variant (Leu55 → Pro)

We report a family with familial amyloid polyneuropathy (FAP), showing an early-onset and a fatal outcome before age 30. Transthyretin (TTR) gene analysis showed one point mutation (T → C change) in the second base of codon 55, and the corresponding amino acid substitution of proline (Pro) for leucine (Leu) was confirmed at the protein level. This is the first FAP family of Taiwanese origin demonstrating a causative gene abnormality, and FAP with TTR-Pro⁵⁵ was considered to be more serious compared with other forms of FAP. © 1994 John Wiley & Sons, Inc.     

A novel benzodiazepine inverse agonist, S-8510, as a cognitive enhancer

1. 1. Pharmacological actions of a novel benzodiazepine receptor ligand, S-8510 (2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano[4,3-b]pyridine monophosphate monohydrate), were examined in in vitro and in vivo studies.

2. 2. S-8510 was characterized as a partial inverse agonist with a modest GABA ratio and low efficacy.

3. 3. S-8510 ameliorated memory impairment induced by cholinergic deficit in the water maze paradigm of Wistar rats.

4. 4. S-8510 augmented LTP of the Schaffer collateral/commissural fiber-CAl synapses in the hippocampal slice preparations of SD rat.

5. 5. S-8510 increased the extracellular levels of acetylcholine and noradrenaline in the hippocampus of Wistar rat.

6. 6. S-8510 selectively potentiated pentylenetetrazol-induced convulsion without affecting minimal electroconvulsive shock- or strychnine-induced convulsion in ddY mice.

7. 7. S-8510 failed to induce any sign of anxiety in the Wistar rat pro-conflict test.

8. 8. S-8510 showed antidepressant-like pharmacological actions in ddY mice.

9. 9. These results suggest that S-8510 can be used as a therapeutic drug for senile dementia, including Alzheimer's disease with little risk for inducing anxiety or convulsion.

     

Hemolytic, lethal and edema-forming activities of the skin secretion from the oriental catfish (Plotosus lineatus)

The crude extract from the skin secretion of the oriental catfish, Plotosus lineatus, contained at least one hemolysin, two lethal factors and two edema-forming factors; the lethal and edema-forming factors seem to be identical. The molecular weights of the hemolysin and the lethal factors (edema-forming factors) were estimated to be 180,000 and 12,000, respectively. Peculiar secretory cells, which resembled the venom glandular cells of the dorsal and pectoral stings, were observed in the epidermis.     

Type I familial amyloidotic polyneuropathy in Japan.

We studied 107 cases and 64 carriers of type I familial amyloidotic polyneuropathy (FAP) residing in 16 districts in Japan. The age of onset of illness ranged from 20 to 71 years old, with a mean of 40.1 +/- 12.8 years (SD). One quarter of the cases were late-onset patients who developed the disorder after age 50. Asymptomatic carriers older than age 50 accounted for 20% of total carriers, with the oldest carrier being a 94-year-old woman. All the patients had a variant transthyretin with a methionine-for-valine substitution at position 30 with a mean serum level of 9.78 +/- 3.27 (SD) mg/dl. The serum level did not significantly differ by gender in either patients or carriers, nor between patients and carriers. Incomplete penetrance of clinical expression was shown in eight cases. This study indicates that there is a considerable variety in age of onset, progression and geographic distribution of type I FAP in Japan.     

Effect of Robaveron tablet (KN-7) in the long-term therapy for urinary disturbances

Long-term therapeutic effect of Robaveron tablet (KN-7) was studied on 10 female patients of middle and old age with ptosis of urinary bladder and 9 patients with neurogenic bladder. The patients had mainly complained of such subjective symptoms as pollakisuria, difficulty of urination, sense of residual urine, lower abdominal discomfort and urinary incontinence. Robaveron tablet was administered at 2 tablets t.i.d. for 3-26 months. And the drug efficacy was evaluated by residual urine, cystometric findings and subjective symptoms. A significant decrease in the residual urine rate and a significant increase of pressure amplitude were obtained, and improvement of subjective symptoms was seen with an effective rate of about 70%. Overall effectiveness, rated slightly improved or better was 89.5%. No cases of side effects or abnormalities in laboratory tests were observed. Robaveron tablet is safe and effective for patients with urinary disturbance accompanied by ptosis of urinary bladder, as a myogenic disorder, as well as neurogenic bladder in the long-term therapy.