Naoki Tokunaga

Urinary trypsin inhibitor: a new drug to treat preterm labor: a comparative study with ritodrine

UNLABELLED Prevention of preterm delivery is one of the difficult problems facing obstetricians. beta Adrenergic agonists, especially ritodrine, are commonly used in these cases. OBJECTIVES The aim of this research was to study and compare the effect of urinary trypsin inhibitor (UTI) which has anti-inflammatory anti-cytokine effects with ritodrine in treating preterm labor. STUDY DESIGN Patients in preterm delivery were randomly selected to be treated either by ritodrine or UTI. In the ritodrine group, uterine contractions were initially suppressed by high doses of ritodrine (up to 300 micrograms/min) and then a maintenance dose was given until 35 weeks of gestation. In the UTI group one vaginal suppository (5000 U) was used daily for 2 weeks. Patients with recurrent preterm uterine contraction during the initial 14 days of treatment, who needed course of other drugs to suppress the contractions, were excluded from the study. Patients responding to the drugs were followed until delivery. Tocolytic index and elastase concentration in the cervical mucus was calculated. Recurrence rate of uterine contraction and time of elongation of pregnancy since the beginning of treatment was calculated. RESULTS UTI was more effective than ritodrine in inhibition of recurrent uterine contraction and elongation of pregnancy. No side effects could be observed after treatment with UTI for the mother or the fetus. CONCLUSION UTI may be a new therapeutic method for the inhibition of preterm delivery through suppression of cytokines and inflammatory mediators.

Urinary trypsin inhibitor suppresses vascular smooth muscle contraction by inhibition of Ca2+ influx.

Urinary trypsin inhibitor (UTI) and its precursor form inter-alpha trypsin inhibitor (ITI) are present in plasma. To determine the action of UTI on blood vessels, we performed isometric vascular muscle contraction tests, microcirculation studies and measurement of cytosolic free Ca2+ in vascular smooth muscle cells. An isometric vascular muscle contraction test showed that the contractions stimulated by endothelin-1 or norepinephrine were suppressed in the presence of UTI, and that the contractions were not inhibited in the presence of ITI. The microcirculation study showed that the contraction of mesenteric arterioles of WKY rats induced by norepinephrine were inhibited by treatment of UTI, and that they did not alter by treatment of ITI. Pre-incubation of UTI, but not ITI, with vascular smooth muscle cells inhibited the increase of cytosolic free Ca2+ induced by endothelin-1 or norepinephrine. Cell-binding study by biotinylated UTI showed that vascular smooth muscle cells have specific binding site for UTI, but not for ITI. We propose that circulating UTI converted from ITI has a regulatory effect on local vascular tone by regulation of Ca2+ influx into smooth muscle cells.

The impact of vasoactive peptides on nitric oxide production in cultured sympathetic neurons.

The concentration of nitric oxide was found to be decreased in a hypersympathetic condition. We carried out experiments on cultured sympathetic neurons from 12-14-days-old chick embryos to investigate the role of vasoactive peptides and amine on nitric oxide production. Stimulation of cultured neurons with endothelin-1, norepinephrine and angiotensin-II initially increases nitric oxide production and subsequently decreases it in a dose-dependent manner (P<0.05, n = 7). Stimulation of Fura-2 acetoxymethyl ester-loaded neurons with endothelin-1, norepinephrine and angiotensin-II increases the calcium influx (within 30-90 s) and it is then restored to the initial level (P<0.05, n = 7). An additional observation was that specific stimulator L-arginine significantly increases the nitric oxide release and calcium influx into the cells, whereas N(W)-nitro-L-arginine methyl ester blunts nitric oxide release dose dependently (P<0.05, n = 7) and does not change the calcium concentration in the cells. We propose that vasoactive peptides and amines inhibit nitric oxide production in the cultured sympathetic neuron by regulation of intracellular calcium concentration.

Dilatation of the Left Renal Vein in Preeclampsia

OBJECTIVE Our purpose was to compare the morphological changes in renal veins during normal pregnancy and pregnancy involving preeclampsia. METHODS We used ultrasonography to measure maximum diameters of the right and left renal veins, and the diameter of the left renal vein where it crosses the abdominal aorta in normal pregnancy and preeclampsia. RESULTS In women with normal pregnancy, the maximum diameter of the left renal vein was 5.5 +/- 1.9 mm in the 1st trimester, 5.8 +/- 1.6 mm in the 2nd trimester, and 6.4 +/- 1.4 mm in the 3rd trimester. The diameter of the left renal vein where it crosses the abdominal aorta was 3.3 +/- 1.1 mm in the 1st trimester, 4.1 +/- 1.3 mm in the 2nd trimester, and 4.0 +/- 0.9 mm in the 3rd trimester. In contrast, the maximum diameter of the left renal vein in women that had preeclampsia with onset in the 2nd trimester was 9.8 +/- 2.4 mm and that in women whose preeclampsia began in the 3rd trimester was 8.7 +/- 1.6 mm. The diameter of the left renal vein in preeclampsia was significantly larger than that in normal pregnancy (P < 0.05). There were no significant differences between normal pregnancy and preeclampsia in the maximum diameter of the right renal vein or that of the left renal vein where it crosses the abdominal aorta. CONCLUSIONS In preeclamptic women, a dilatation of the left renal vein was observed. This suggests that the relative constriction and congestion of the left renal vein takes part in the pathophysiology of preeclampsia. Measurement of the diameter of the left renal vein would provide a simple, cost-effective tool for the diagnosis of preeclampsia.

Hypolumbarlordosis: a predisposing factor for preeclampsia

OBJECTIVE The aim of this research was to study the relationship between lumbar lordosis and preeclampsia. STUDY DESIGN We studied lumbar lordosis of 52 primipara patients with pregnancy-induced hypertension and 59 normal primipara pregnant women. We determined the lumbar lordotic deviation (LLD) from lumbar lordosis measurement device in the lateral recumbent position and standing position. Roll-over test was performed for both groups. Resistance index (RI) of internal iliac artery was also measured by color Doppler sonography. RESULTS The LLD was 33 +/- 6.1 degrees week 20-29 and 34 +/- 6.9 degrees week 30-40, respectively. In patients with preeclampsia, the LLD was 19.8 +/- 6.3 degrees week 20-29, 21.3 +/- 7.9 degrees week 30-40. The LLD in patients with preeclampsia was significantly lower than in the normal pregnant women. The LLD correlated to the increase diastolic pressure after roll-over test significantly. Hypolumbarlordosis was frequently associated with high resistance of peripheral vessel. CONCLUSIONS We conclude that hypolumbarlordosis is frequently associated with preeclampsia. It is also closely related to the mechanism for positive roll-over test and increase of resistance of vessels. As lumbar lordosis does not change greatly in individuals before pregnancy, hypolumbarlordosis may be a predisposing factor for preeclampsia.

An autopsy case of cyclopia with 13 trisomy with special reference to histological abnormalities of the eyeball

ABSTRACT We present an autopsy case of cyclopia and alobar holoprosencephaly and Polydactyly with 13 trisomy. A 27 year‐old Japanese female at the 27th gestational week was diagnosed as hydramnios and the fetus showed hydrocephalus and intrauterine growth retardation. The fetus was suspected to be cyclopic and holoproscncephalic by ultrasonograph and MRI images. The mother delivered a stillborn male baby at the 30th week of gestation. At autopsy, the baby showed true cyclopia having one eyeball and two irides in a single ocular opening, and one proboscis. On histological analysis of the eye, there was marked dysplastic hyperplasia of the retina with rosettes, focal degeneration of the retina with calcification, and prominent proliferation of glial cells beneath the hyperplastic retina. Multiple glomerular structures in the cerebral cortex and aplasia of the corticospinal tract were observed. In the spinal cord, a few neurons with pyknosis were observed in the ventral horn. Although no mutation was detected in the Sonic hedgehog in the present case, we reviewed recent studies concerning the molecular mechanisms of cyclopia and holoprosencephaly.