Management of pregnancy with congenital antithrombin III deficiency: two case reports and a review of the literature.

Women with antithrombin (AT) III deficiency are prone to pregnancy-associated venous thromboembolism. We report 2 cases with genetically confirmed ATIII deficiency, one with a mutation in exon 3A and the other with an exon 4 deletion, in whom the pregnancies were successfully managed with prophylactic therapies for thrombosis. A 35-year-old pregnant woman was treated with intravenous infusions of ATIII concentrate alone, and the other 22-year-old pregnant woman was mainly treated with subcutaneous injections of heparin and oral low-dose aspirin therapy. Both pregnancies resulted in vaginal deliveries of healthy neonates. The literature concerning prophylactic therapies for thrombosis in ATIII deficiency-complicated pregnancy is reviewed, and the clinical problems, including the adverse effects of the therapies, are discussed.

Radical fringe negatively modulates Notch signaling in postmitotic neurons of the rat brain.

Fringe was originally identified as a novel secreted signaling protein with a key role in wing formation of Drosophila. Three vertebrate fringe homologues, Radical, Lunatic and Manic fringe, were also identified, and have been shown to play major roles in neurogenesis during development. However, the expression and roles of vertebrate fringe homologues in the adult brain remain to be elucidated. We isolated the cDNA encoding rat Radical fringe (334 amino acids) from rat embryos, and found its mRNA to be most abundantly expressed in the adult rat brain by Northern blotting analysis. The localization of Radical fringe mRNA in the adult rat brain was also examined by in situ hybridization. The mRNA was abundantly expressed in most neurons, but not glial cells, throughout the brain. Notch signaling was shown to negatively modulate the stability of neurites and connections in postmitotic primary neurons. Furthermore, genetic evidence indicated that fringe modulated the Notch signaling pathway. Therefore, we examined the effects of Radical fringe on the Notch signaling pathway in primary rat neurons of the cerebral cortex using recombinant rat Radical fringe protein. Radical fringe protein significantly inhibited expression of the Notch effector Hes1 mRNA in primary neurons. These results indicated that Radical fringe functions by inhibiting Notch signaling in postmitotic neurons of the brain.

[A preliminary study of percutaneous ethanol injection therapy for hepatocellular carcinoma: evaluation of the ethanol diffusion area by the ethanol mixed with gadolinium].

To evaluate the ethanol diffusion area after Lipoidalization in 3 patients with advanced HCC treated by Lipoidalization-PEIT combination therapy, 99.9% ethanol mixed with Gadolinium was used for PEIT (Gd-PEIT). T1-weighted MR images wear obtained 1 hr after Gd-PEIT. The area of homogeneous hyperintense change on T1-weighted MR images was taken to be the ethanol diffusion area. In all 3 patients, homogeneous hyperintensity throughout the tumor over the capsule was recognized on T1-weighted MR images after treatment. The results suggests that T1-weighted MR images after Gd-PEIT provide a valuable tool by which to directly evaluate the ethanol diffusion area for advanced HCC treated by Lipoidalization followed by PEIT.

Age-related change of technetium-99m-HMDP distribution in the skeleton.

UNLABELLED: To understand age-related changes of whole-body and regional skeletal metabolism, it is important to investigate the mechanisms of age-related bone loss and to develop suitable treatments for it. Bone biopsies show metabolism of the particular site examined while biochemical markers for bone metabolism reflect total skeletal metabolism. Bone scintigraphy is a convenient and simple way to analyze whole-body and regional skeletal metabolism. We attempted to study and understand age-related changes in bone metabolism by quantifying the bone scan and correlating it with biochemical bone metabolic markers. METHODS: The whole-body skeletal uptake (WBSU) and tracer distribution pattern were studied in men and women by bone scintigraphy using 99mTc-hydroxy-methane-diphosphonate (HMDP). Bone scans were performed using a standard protocol and quantified by setting regions of interest (ROIs) on selected regions. WBSU and the skeletal distribution pattern were compared with simultaneously obtained serum biochemical markers. RESULTS: WBSU showed an increase with age in both sexes, but in women, uptake in the head and legs increased more relatively than in the thoracic region, while in men no such tendency was observed. Increase of WBSU and relative increase of uptakes in the head demonstrated a weak correlation with the serum levels of alkaline phosphatase and type 1 collagen metabolites. CONCLUSION: These results show an age-related increase of skeletal turnover and sex-dependent regional skeletal metabolism. The age-related changes seen in bone scintigrams might be a sign of progressive bone loss, reflecting changes in local bone metabolism.

Estimation of bone mineral density and bone loss by means of bone metabolic markers in postmenopausal women.

We have examined healthy women (51 premenopausal women and 30 postmenopausal women; age 28-59) for lumbar bone mineral density (BMD) by dual energy X-ray absorptiometry (DXA) and assessed metabolic bone markers, such as type I procollagen carboxy-terminal propeptide (P1CP), pyridinoline (PYR), deoxypyridinoline (DPYR), osteocalcin (BGP) and alkaline phosphatase (ALP). BMD was assessed once a year in three consecutive years. Correlations among the BMD, BMD changes and levels of bone markers in samples at the first DXA assessment were studied. In pre-menopausal women, none of the biochemical markers were correlated with the BMD or changes in BMD. In contrast, BMD in post-menopausal women correlated (negatively) well with levels of P1CP, DPYR, PYR and ALP declining in this order, and a significant positive correlation was observed between the rate of bone loss in postmenopausal women and the P1CP concentration. PYR and DPYR also had a tendency to correlate. Combinations of several bone markers improved the correlation. These results show that by measuring several bone specific biochemical markers in postmenopausal women, one can estimate their rates of bone loss as well as their present BMDs. The measurement of biochemical bone markers will therefore be very useful in evaluating bone status and would be applicable in screening postmenopausal osteopenia.

Chronic intramedullary infusion of prostaglandin E2 stimulates bone formation both in the bone marrow and in the periosteum.

Prostaglandin E2 (PGE2) has a potent bone resorbing activity in vitro, but some recent studies have shown that PGE2 stimulates bone formation in vivo. The effects of PGE2 on the bone are therefore still controversial. We attempted to reveal the effects of PGE2 on bone in vivo more directly; we injected PGE2 continuously into the bone marrow and onto the periosteum and examined the local effects of PGE2 histologically or by bone densitometry. Following PGE2 infusion into the bone marrow, new bone was formed in the bone marrow around the infused site and following PGE2 infusion onto the periosteum, extensive periosteal bone formation was observed. Bone mineral content was also increased significantly in the PGE2 infused bones. The administration of cyclic AMP did not mimic the effects of PGE2. In contrast to in vitro experiments, the in vivo effect of PGE2 is predominantly to produce bone.

[Radioimmunoassay for the pyridinoline cross-linked carboxy-terminal telopeptide of type 1 collagen (1CTP)--some basic aspects of the RIA kit and clinical evaluation in various bone diseases].

A radioimmunoassay for circulating levels of the pyridinoline cross-linked carboxy-terminal telopeptide of type 1 collagen (1CTP) was developed and can be available as a kit on a commercial base. Using the kits, we evaluated basically and clinically the assay. The assayed values were reproducible and the assay can detect as low as 0.5 ng/ml of 1CTP. In healthy volunteers, circulating level was high under age 24 and over age 46. In patients with bone metastasis, serum levels elevated even in its early stage and correlated well with clinical status. In other bone diseases, such as primary hyperparathyroidism, hyperthyroidism, post-gastrectomy, hypercalcemia of malignancy and myeloma, serum levels elevated according to their clinical conditions. In patients with chronic renal failure, serum levels were high, suggesting decrease of renal clearance of 1CTP. The circulating 1CTP levels seemed to reflect well clinical bone destructive status. A high correlation between serum 1CTP level and urinary pyridinoline (r = 0.884) was shown, whereas essentially no correlation was observed between bone formation markers such as osteocalcin and alkaline phosphatase. Thus, the measurement of circulating 1CTP seems to be a simple and sensitive method to monitor bone destruction.

[Clinical evaluation of ultrasonic measurement of the calcaneal bone].

We measured the speed of sound (SOS) and broadband ultrasound attenuation (BUA) in the calcaneal bone and compared those values with bone mineral density (BMD) as assessed by single X-ray absorptiometry and dual energy X-ray absorptiometry. Calcaneal speed of sound and broad band ultrasound attenuation showed an earlier decrease with age than lumbar BMD, Calcaneal SOS and BUA correlated well with calcaneal BMD. Calcaneal SOS correlated more closely with neck BMD than lumbar BMD measured by DXA. Furthermore, measurement of calcaneal SOS is more useful than measurement of lumbar BMD to evaluate femoral neck BMD, which might be very important for clinical purposes. Both body weight and height correlated well with calcaneal BMD but not so well with calcaneal SOS or BUA. As ultrasound emits no radiation, we can use it without the restriction of radiation protection.

[Measurement of serum concentration with radioimmunoassay for carboxyterminal propeptide of type 1 procollagen].

A radioimmunoassay kit for measurement of carboxyterminal propeptide of type 1 procollagen (P1CP) was developed and can be purchased commercially for clinical use. Using the kit, we measured serum concentration in healthy controls and in patients with bone metastasis and other various skeletal disorders. In healthy controls, serum concentration of P1CP ranged within 37-177 ng/ml under age 50, while in serum concentration of women over 50, it elevated upto 350 ng/ml. In patients with skeletal metastasis, in most of patients, it stayed within a normal range, whereas in patients with bone metastasis from prostatic cancer, it raised significantly. In some of patients with primary hyperparathyroidism or hyperthyroidism, serum concentration for P1CP was also elevated. In comparison with other serum bone metabolic markers such as osteocalcin or alkaline phosphatase, P1CP showed less occurrence of an elevation in patients with non-skeletal disease. Serum concentration of P1CP was not affected by renal function, while mild elevation was observed in patients with severely damaged liver diseases. In conclusion, the newly developed radioimmunoassay for P1CP was an excellent assay system and would provide us easily evaluation of type 1 collagen formation.

[Hypervitaminosis D].

Excessive vitamin D causes marked and prolonged hypercalcemia by accelerating intestinal calcium absorption and bone resorption. Vitamin D induced hypercalcemia includes the toxic ingestion of excessive amount of vitamin D preparations, granulomatous diseases and lymphoproliferative malignancies. In vitamin D toxicity, the clinical courses vary depending on the vitamin D preparation responsible for the hypercalcemia. Hypercalcemia state continues for several months when D2 or D3 are responsible for the toxicity whereas the hypercalcemia would subside in a week when 1 alpha(OH) D3 or 1,25 (OH)2D3 are responsible for the toxicity. Abnormal calcium metabolism can be treated by hydration and glucocorticoids. Hypercalcemia is associated with variety kinds of granulomatous diseases, including sarcoidosis and tuberculosis. The granulomatous tissue is believed to be the site of the ectopic production of 1,25(OH)2D3 in which the regulation of the synthesis is quite different from that in the normal kidney. Glucocorticoid markedly diminishes the synthesis. Hypercalcemia associated with elevated serum 1.25(OH)2D3 levels is also found in patients with lymphomas and some other malignancies. However, there still are not sufficient evidences to prove that the excessive amount of endogenous 1.25(OH)2D3 is the primary cause of the hypercalcemia.

[Determination of vertebral fracture threshold by measuring bone mineral content in the lumbar vertebrae].

Bone mineral density (BMD) in the lumbar vertebrae (L2-L4) was assessed by dual energy X-ray absorptiometry (DEXA: QDR-1000), and the values obtained were compared with the frequency of vertebral fracture as assessed by spinal X-ray photographs. Patients with spondylosis or scoliosis, which affect BMD values, were excluded from the study. An essentially linear correlation was observed between the frequency of vertebral fracture and lumbar BMD values: no vertebral fractures were observed in those whose BMD more than 0.8 g/cm2, whereas the frequency of fracture was 100% in patients whose BMD was less than 0.45 g/cm2. Thus, measurement of lumbar vertebrae by DEXA would be very useful in predicting vertebral fractures.

Pulmonary metastatic nodules: CT-pathologic correlation.

To elucidate the characteristics of pulmonary metastatic nodules on high-resolution computed tomographic (HRCT) scans, a correlative computed tomographic (CT)-pathologic study was performed with five human lungs after autopsy. The relationship of metastatic nodules to pulmonary vessels was studied with HRCT scans, radiographs of the specimen, and stereomicroscopic study in 264 nodules 0.6-9.0 mm in diameter. On radiographs and stereomicroscopic images, 190 small nodules (less than 3 mm in diameter) were in contact with the pulmonary lobule on the central bronchovascular bundles (n = 33 [17.4%]), located between the central bronchovascular bundle and the perilobular structure (n = 127 [66.8%]), or attached to perilobular structures (n = 30 [15.8%]). On HRCT scans, 21 small nodules (11.1%) were located on the central bronchovascular bundle; 130 small nodules (68.4%), between the central bronchovascular bundle and the perilobular structure; and 39 small nodules (20.5%), on the perilobular structure. On radiographs and stereomicroscopic images, 43 of 74 large nodules (greater than 3 mm in diameter) (58%) compressed both bronchovascular bundles and perilobular structures. The central bronchovascular bundle was invaded in only 13 large nodules (18%).

Dihydropyrimidines: novel calcium antagonists with potent and long-lasting vasodilative and antihypertensive activity.

The novel calcium antagonists 3-N-substituted-3,4-dihydropyrimidines 1 and 9 and 3-N-substituted-dihydro-pyrimidin-2(1H)-ones 8 were regioselectively synthesized in good yields. Compounds 1 [especially 1s [R1 = (CH2)2N(benzyl)(2-naphthylmethyl), R2 = i-Pr, X = 0-NO2] and 1t [R1 = (CH2)2N(benzyl)(3,4-dichlorobenzyl), R2 = i-Pr, X = 0-NO2]] exhibited not only more potent and longer lasting vasodilative action but also a hypotensive activity with slow onset as compared with dihydropyridines. Moreover, some dihydropyrimidines [1q [R1 = (CH2)2N(benzyl)(3-phenylpropyl), R2 = CH2(cyclopropyl), X = 0-NO2], 1s, and 1t] were weaker in blocking atrioventricular conduction in anesthetized open-chest dogs and less toxic than the dihydropyridines.