Effect of endogenous vasoconstrictors on maternal intramyometrial and fetal stem villous arteries in pre-eclampsia.

The contractile responses to various endogenous vasoactive agents were investigated in isolated human uteroplacental arteries from normotensive (NT) patients and patients with pre-eclampsia (PE) undergoing caesarian section. Tissue samples were obtained from the uterine incision and from macroscopically normal cotyledons. Vascular ring preparations of intramyometrial and stem villous arteries (length 1.0-1.3 mm, outer diameter 400-600 microns) were dissected and mounted in organ baths and isometric tension was recorded. Concentration-response relationships for vasopressin (VP), oxytocin (OX), angiotensin II (Ang II), noradrenaline (NA), 5-hydroxytryptamine (5-HT), prostaglandin F2 alpha (PGF2 alpha) and prostaglandin E2 (PGE2) were assessed. For each compound, the mean maximum contractile effect (Emax) and the drug concentration producing half-maximal response (EC50) were determined. In intramyometrial arteries from NT and PE patients, VP, Ang II, NA, 5-HT and PGF2 alpha induced contraction while OX and PGE2 produced weak or no responses. Preparations from PE patients showed higher Emax values, while no differences in EC50 were found between the two groups. In fetal stem villous arteries, Ang II, 5-HT, PGF2 alpha and PGE2 induced contractions, while VP, NA and OX produced weak responses. No differences in Emax or EC50 values were found between the fetal vessels of PE and NT patients. No qualitative differences were demonstrated in response to the agents tested between the vessels (fetal and maternal) from NT women at term and PE patients. However, the results may reflect quantitative differences, suggesting increased contractility of maternal uteroplacental arteries from women with PE.

Relaxant effects of hexosamines on isolated small human placental arteries.

Wharton's jelly contains large amounts of hyaluronic acid, and glucosamine is an important constituent of this macromolecule. In order to evaluate the placental vascular effects of this aminosugar, small chorionic and stem villous arteries were dissected from placental specimens obtained at normal term vaginal deliveries (n = 15). Ring preparations were mounted in organ baths, and isometric wall tensions were measured. Glucosamine and its epimer galactosamine (5 X 10(-4) to 10(-2) M) produced marked relaxation of contractions induced by PGF2 alpha (10(-5) M) in both chorionic and stem villous arteries. The effect was unchanged after pretreatment with atropin, propranolol and indomethacin. The relaxant effect of the neutral sugar mannose was less pronounced compared with that of the hexosamines. Total tissue concentrations of placental hexosamines have been reported within the range needed to produce placental vascular relaxation in the present study. However, the major part of these compounds is integrated in macromolecules, and the tissue level of free hexosamine is probably far below the total concentrations. Accordingly, the effects of hexosamines demonstrated in the present study might not be of physiological importance in the regulation of fetal placental medial smooth muscle tension.

Effects of vasoactive intestinal polypeptide and substance P on human intramyometrial arteries and stem villous arteries in term pregnancy.

The effects of vasoactive intestinal polypeptide (VIP) and substance P on isolated human intramyometrial arteries and fetal stem villous arteries obtained from term pregnant women were compared. Ring preparations of small intramyometrial arteries and fetal stem villous arteries obtained at caesarean section were mounted in organ baths, and isometric tension was recorded. None of the peptides affected resting tension. In intramyometrial arteries precontracted by vasopressin (2.8 x 10(-9) M) both substance P (10(-12) to 10(-8) M) and VIP (10(-8) to 10(-6) M) caused relaxation. In fetal stem villous arteries precontracted by prostaglandin F2 alpha (10(-5) M) cumulative addition of substance P (10(-11) to 10(-6) M) did not produce significant changes in tension as compared with controls, while addition of single doses produced moderate relaxation. VIP (10(-8) to 10(-6) M) induced relaxation with similar effects for the addition of cumulative and single doses. The responses to VIP and substance P remained unaffected after pretreatment by atropine (10(-6) M), propranolol (10(-6) M), and indomethacin (10(-6) M). The results support a role for VIP and substance P in the regulation of uteroplacental blood flow in term pregnancy.

Digoxin inhibition of relaxation induced by prostacyclin and vasoactive intestinal polypeptide in small human placental arteries.

Small chorionic plate arteries were obtained from human placentae following normal vaginal delivery. Tubal vascular preparations were dissected, mounted in organ baths, and their isometric tension was recorded. Digoxin (10(-6) M) caused a rise in basic tension, reaching a maximum of 17 per cent of contractions induced by potassium (124 mM) depolarization. Pretreatment with digoxin did not significantly influence the concentration-dependent contractile responses to 5-hydroxytryptamine and prostaglandin F2 alpha (PGF2 alpha). In preparations contracted with PGF2 alpha, cumulative addition of prostacyclin (PGI2) and vasoactive intestinal polypeptide (VIP) produced concentration dependent relaxations. Digoxin (10(-8) to 10(-6) M) inhibited and finally abolished these relaxant effects of PGI2 and VIP in a concentration-dependent fashion. Pretreatment by digoxin (10(-8) to 10(-6) M) diminished the relaxant effect of sodium nitroprusside, but the effect was less pronounced than that on PGI2- and VIP-induced relaxation. As PGI2 and VIP may be of importance for the maintenance of a low resistance of the fetal placental vascular bed, the finding that digoxin decreases the vasodilating effects of these agents might imply effects on placental resistance of cardiac glycosides when used in late human pregnancy.

Effects of vasodilators on isolated human uteroplacental arteries.

The effects of the vasodilator drugs hydralazine, labetalol, prazosin, and nitrendipine were studied on responses to K+ (124 mmol/L), noradrenaline, vasopressin, and angiotensin II in small human maternal intramyometrial arteries and on responses to K+, prostaglandin (PG) F2 alpha, and angiotensin II in fetal stem villous arteries. The vessels were dissected from biopsy specimens obtained during term cesareans and mounted in organ baths. Hydralazine failed to inhibit responses to any of the agonists tested in the fetal and maternal arteries. Labetalol and prazosin decreased responses to noradrenaline but did not affect contractions induced by the other agonists in maternal arteries. In fetal arteries, which did not respond to noradrenaline, no effects of labetalol and prazosin were found. Nitrendipine inhibited responses to all the agonists tested in maternal arteries. In fetal preparations, the drug decreased responses to K+ and PGF2 alpha but did not affect contractions induced by angiotensin II. Vasodilator drugs applied for treatment of pregnancy-induced hypertension show differential effects on human maternal and fetal uteroplacental arteries, depending on their mode of action and the agonists responsible for the contractile activation in these vessels.

Cinoxacin in urinary tract infections. Theoretical and practical considerations.

In dogs we found that cinoxacin concentrations in prostatic tissue, secretion, and interstitial fluid always were lower than the simultaneous serum concentrations, during constant infusion experiments. The cinoxacin concentrations in urethral and vaginal secretions were similar to those found in prostatic interstitial fluid, approximately one third to one fourth of the simultaneous serum concentrations. The concentrations of cinoxacin in human prostatic tissue after single or multiple doses of 500 mg. were found to be in the range of minimum inhibitory concentrations for most microorganisms found in urinary tract infections. Cinoxacin was found to have a half-life of 2.7 hours in patients with normal renal function, but increased to 8.5 hours in patients with impaired renal function. We found little or no drug accumulation during a seven-day treatment of patients with impaired renal function.

[In vitro fertilization and embryo transfer at the community hospital in Arhus]. / In vitro fertilisation og embryotransferering ved Arhus Kommunehospital.

Treatment of tubal infertility with in vitro fertilization and embryo transfer (IVF-ET) was introduced in the gynaecological/obstetric department of Arhus Municipal Hospital in February 1988. The principles of treatment are described. During the first ten months, 305 therapeutic cycles were carried out and clinical pregnancy occurred in 20.2% of the cycli after transfer of pre-embryos.

[Transabdominal chorion villus biopsy following abnormal ultrasonic findings in the second trimester]. / Transabdominal chorion villus biopsi ved abnormt ultralydfund i 2. trimester.

If oligohydramnios, growth retardation or foetal malformations are demonstrated by ultrasonic scanning in the second or third trimesters, this implies that the risk of chromosome anomalies is significantly increased. In cases such as these, determination of the foetal karyotype may therefore be indicated. Until recently, amniocentesis has been employed for this but the results of the chromosome investigation are not available until two to three weeks after the intervention. The delay between amniocentesis and the result of chromosome investigation imposes a mental strain on the pregnant woman. Three patients with abnormal ultrasonic findings in the second trimester were, therefore, submitted to transabdominal chorion villus biopsy and, in all three cases, a karyotype was available within 48 hours. Chorion villus biopsy in the second (and third) trimester is indicated in pregnancies in which oligohydramnios, growth retardation or foetal malformations have been demonstrated by ultrasonic scanning, in cases where referral for antenatal diagnosis is very late and when chromosome investigation after amniocentesis proves unsuccessful and repeated amniocentesis would result in an unacceptably late result.

[Heterotopic pregnancy after in vitro fertilization]. / Heterotop graviditet efter in vitro fertilisering.

Until December 1991, 1171 pregnancies had been established in Denmark after in vitro fertilization and embryo transfer (IVF-ET). Thirteen of these pregnancies were heterotopic (1.1%). Three patients were asymptomatic, four patients presented with an acute abdomen, five had abdominal pain and only two patients had vaginal bleeding. In five cases the diagnosis of heterotopic pregnancy was made by ultrasound, while eight cases were diagnosed at the time of surgery. Eleven patients were treated in the first trimester, while two patients were treated at 23 and 38 weeks of gestation, respectively. In nine of the thirteen cases the intrauterine pregnancy resulted in term delivery. Heterotopic pregnancy occurred in 1% of pregnancies following IVF-ET. Abdominal pain was the predominant symptom, while vaginal bleeding was absent in the majority of women. In most cases removal of the ectopic gestation allowed the intrauterine pregnancy to proceed until term.

[Fertilization in vitro. A review over the medical indications and suggestion to unified guidelines for public fertility clinics in Denmark]. / In vitro fertilisering. En oversigt over medicinske indikationer og forslag til foelles retningslinier ved de offentlige danske fertilitetsklinikker.

Medical indications for in vitro fertilization and embryo transfer (IVF-ET) internationally and in Denmark are reviewed. Reports from large international centres document that tubal infertility, unexplained infertility, endometriosis and male infertility are equally good indications for IVF. Traditionally, tubal infertility has been the only medical indication qualifying for IVF treatment within the National Health Service in Denmark. Thus, in this country, couples with unexplained and male infertility and with endometriosis have to pay up to 25,000 D.Kr. per IVF-ET treatment in private fertility clinics. Since there is no scientific basis for this discrimination, it is urged that the present rules are changed, so that couples with unexplained and male infertility and endometriosis are also allowed IVF treatment free of charge in the public fertility clinics.

[Ovum donation. A review of and a suggestion to unified guidelines for treatment at public fertility clinics in Denmark]. / Aegdonation. En oversigt samt forslag til foelles retningslinier for behandling ved de offentlige danske fertilitetsklinikker.

The most common indication for oocyte donation is ovarian insufficiency due to premature menopause or resistant ovarian syndrome and ovarian dysgenesis with either normal or abnormal (e.g. Turner's syndrome) karyotype. In Denmark, oocyte donation must be anonymous, and the donors have to be other infertile patients undergoing in vitro fertilisation (IVF), treatment. It is suggested, that the National Health Service offers oocyte donation to hypergonadotropic women with ovarian insufficiency, as well as to a few other groups who fulfil the criteria for IVF treatment, but where this treatment cannot be completed. Oocyte donors must be less than 35 years old, physically and mentally healthy and without major genetic diseases in the family. The donor must be screened for HIV, hepatitis, syphilis, chlamydia and gonorrhoea. We propose that those patients who have more than six oocytes aspirated, allowing "surplus" oocytes to be donated. It is also proposed that the departmental order from the Ministry of Health be changed, so that normally fertile women are allowed to donate oocytes. Oocyte donation should be reported to a central authority.

[Freezing of human embryos. A review of and a suggestion to unified guidelines for treatment at public fertility clinics in Denmark]. / Nedfrysning af menneskelige aeg. En oversigt samt forslag til faelles retningslinier for behandling ved de offentlige danske fertilitetsklinikker.

In Denmark, legislation has made cryopreservation of human oocytes and embryos possible since October 1992. The legislation is reviewed. Cryopreservation of embryos constitutes a significant improvement of infertility treatment. The number of oocyte pick-ups and the number of embryos transferred can be reduced without compromising the total likelihood of success of in-vitro fertilization (IVF) treatment. According to Danish law, frozen embryos can only be stored for one year. This limit will interfere with patient expectations in numerous cases, and the time limit should be expanded. Moreover, freezing of embryos should be allowed in connection with oocyte donation programmes.

Rifampin and trimethoprim distribution in normal and hydronephrotic kidney and in prostate: an experimental study in dogs.

Concentrations of rifampin and trimethoprim, administered in the ratio 3.75:1 were measured in renal hilar lymph, renal interstitial fluid, prostatic interstitial fluid and prostatic secretion in dogs during constant infusion of the antibiotic combination. The lymph was obtained by direct cannulation of the lymphatics and the interstitial fluids from small plastic tissue chambers implanted 4 weeks before the experiments. Unilateral hydronephrosis was produced by ureteral ligation in dogs with tissue chambers in both kidneys to compare concentrations of the drug combination in renal interstitial fluid and urine from normal and hydronephrotic kidneys. Rifampin produced lower concentrations in both prostatic interstitial fluid and prostatic secretion than in plasma, while trimethoprim concentrations were much higher in prostatic secretion and prostatic interstitial fluid than in plasma. Renal lymph/plasma ratios and renal interstitial fluid/plasma ratios were significantly higher for trimethoprim than for rifampin, but only the lymph concentrations of trimethoprim exceeded the corresponding plasma concentrations. High urine concentrations were achieved for both drugs except in pelvises of hydronephrotic kidneys, where virtually no drug activity could be detected. Renal interstitial fluid concentrations of both drugs were similar in hydronephrotic and normal kidneys. The ratios between rifampin and trimethoprim concentrations varied considerably among plasma, various tissues and tissue fluids.

Differential effects of angiotensin, vasopressin and oxytocin on various smooth muscle tissues within the human uteroplacental unit.

Tissue specimens from various parts of the uteroplacental unit were obtained from women undergoing caesarean section, and placental tissue from women with normal deliveries. Strips of myometrial tissue, and segments of intramyometrial arteries were dissected together with segments of chorionic plate arteries and veins, and stem villous arteries. The preparations were mounted in organ baths, isometric tension recorded, and the responses to angiotensin II, vasopressin, and oxytocin were studied. In myometrial preparations, angiotensin caused a slight, transient increase in the frequency of spontaneous contractions, but no changes in amplitude. In all vascular preparations angiotensin produced concentration-related contractions. The responsiveness of the preparations was myometrial artery greater than villous artery greater than chorionic plate artery = chorionic plate vein. All responses were transient and tachyphylaxis was pronounced in all tissues. Tachyphylaxis was not influenced by pretreatment with indomethacin. Vasopressin increased transiently frequency and amplitude of contractions in myometrial strips. Myometrial arteries responded with a sustained contraction, as did chorionic plate arteries and veins but the latter vessels were less responsive. Villous arteries did not respond to vasopressin. Oxytocin preferentially stimulated myometrial strips, but also had a weak concentration-related contractant effect on chorionic plate arteries and veins. Villous arteries did not respond to oxytocin. At a higher concentration, causing a pronounced increase in the frequency and amplitude of contractions of myometrial strips, oxytocin abruptly caused a marked contraction of myometrial arteries. Lower concentrations of the peptide had almost no effects. The results suggest that various smooth muscle tissues of the human uterus and placenta are highly differentiated as regards responses to angiotensin II, vasopressin, and oxytocin. The physiological and possible clinical importance of the present findings deserve further investigation.

Relaxant and contractile effects of some amines and prostanoids in myometrial and vascular smooth muscle within the human uteroplacental unit.

Tissue specimens of human myometrium and placenta were obtained at caesarean section and normal vaginal deliveries. Strips of myometrial tissue, and segments of intramyometrial arteries, chorionic plate arteries and veins, and stem villous arteries were dissected. The preparations were mounted in organ baths, and isometric tension was recorded. In myometrial preparations, prostaglandin F2 alpha (PGF2 alpha), prostaglandin E2 (PGE2), noradrenaline (NA) and serotonin (5-HT) all caused concentration-related contractions. In vascular preparations, the maximum contractant or relaxant effect, Emax or Imax, and the drug concentrations causing half maximum responses, EC50 or IC50 were determined. In intramyometrial arteries no significant differences between Emax or EC50 values were found for NA, 5-HT and PGF2 alpha. The Imax values (relaxation of vessels contracted by vasopressin) ranged prostacyclin (PGI2) greater than PGF2 alpha = PGE2, and the IC50 values PGF2 alpha = PGE2 = PGI2 (PGF2 alpha less than PGI2). Thus, PGF2 alpha showed dual effects. Only PGI2 relaxed placental vessels contracted by PGF2 alpha. In chorionic arteries, Emax values ranged PGE2 = PGF2 alpha greater than 5-HT greater than NA, and IC50 values 5-HT less than NA = PGF2 alpha = PGE2. In stem villous arteries, Emax ranged PGE2 = PGF2 alpha greater than 5-HT = NA, and EC50 5-HT = NA = PGE2 = PGF2 alpha. In chorionic veins the order of Emax values was PGF2 alpha = PGE2 greater than 5-HT greater than NA, and that of the EC50 values 5-HT less than NA = PGF2 alpha = PGE2. Smooth muscle tissues from the human uteroplacental unit show individual responses to prostanoids and amines, probably reflecting individual mechanisms for control of contractile activity and blood flow.

Effects of nifedipine on human placental arteries.

Small chorionic plate arteries (outer diameter 600-700 micron) and umbilical arteries were obtained from human placentas following normal vaginal delivery. Tubal vascular preparations were dissected, mounted in organ baths, and isometric tension was recorded. None of the preparations developed spontaneous contractile activity. The course of potassium-induced contractions differed between chorionic and umbilical arteries. The chorionic arteries showed decreased response to 5-hydroxytryptamine (5-HT) as compared to the umbilical arteries, whereas the contractile response to prostaglandin F2 alpha (PGF2 alpha) was equal. In the chorionic arteries, nifedipine effectively inhibited potassium-induced contractions and, at concentrations of 10(-8)-10(-6) M, decreased responses to 5-HT and PGF2 alpha. Removal of extracellular calcium almost abolished the response to high potassium and reduced the response to both PGF2 alpha and 5-HT by 65%. Nifedipine (10(-8) M) significantly reduced, and nifedipine (10(-7) M) almost abolished, the contractile response induced by calcium after K+ (124 mM) depolarization, and in the presence of PGF2 alpha and 5-HT, nifedipine (10(-8)-10(-7) M) effectively depressed the responses to calcium. The results show decreased response to 5-HT with decreasing dimensions of the placental vessels, and suggest that small placental vessels utilize multiple sources of calcium for contractile responses. Nifedipine seems to interfere with some of these mechanisms and clinical use of the drug may imply a decreased fetal placental vascular resistance.

Concentrations and contractile effects of substance P in the human ampullary-isthmic junction.

From 20 women undergoing hysterectomy, strip preparations were isolated from the outer, longitudinal and the inner, circular smooth muscle layer of the ampullary-isthmic junction (AIJ), together with small arterial segments dissected as ring preparations from the root of the mesosalpinx. The specimens were mounted in organ baths and isometric tension was recorded. In addition, tissue concentrations of substance P (SP) in the ampulla, AIJ and utero-tubal junction were determined by radioimmunoassay. Tissue concentrations of SP expressed as pmol X g tissue-1 (wet weight, +/- SE) amounted to 3.09 +/- 1.40 in the utero-tubal junction, 1.08 +/- 0.299 in the AIJ and 0.742 +/- 0.299 in the ampulla. In strips of circular muscle, SP at concentrations of 10(-7) -3 X 10(-6) mol X l-1 elicited a combined phasic and tonic response and in longitudinal muscle a mainly tonic contraction was produced. In both tissues, contractions elicited by SP were rapidly abolished in calcium-free medium. Nifedipine abolished the phasic contraction elicited in circular muscle by SP while the tonic response was resistant. The contraction in longitudinal muscle was reduced by 20-30%. Vasoactive intestinal polypeptide (VIP) decreased tension in preparations contracted by SP, prostaglandin F2 alpha and K+-depolarization (124 mmol X l(-1). In unstimulated oviductal arterial preparations, SP had no effect, while the peptide induced a transient relaxation of noradrenaline contracted preparations, and slightly decreased tension of K+-depolarized vessels. The results suggest that SP may be involved in the control of motility of the human AIJ.

Course and treatment of milk stasis, noninfectious inflammation of the breast, and infectious mastitis in nursing women.

In nursing women with inflammatory symptoms of the breast, it has been possible on the basis of leukocyte counts of the milk and quantitative cultivation for bacteria to classify these cases into milk stasis (counts of less than 10(6) leukocytes and less than 10(3) bacteria per milliliter of milk), noninfectious inflammation (counts of greater than 10(6) leukocytes and less than 10(3) bacteria), and infectious mastitis (counts of greater than 10(6) leukocytes and greater than 10(3) bacteria). In the present study the duration and outcome of these cases were observed, and those without intervention were compared to those with treatment that consisted of systematic and intensive emptying of the breast, supplemented in some cases by antibiotic therapy as directed by susceptibility tests of the bacteria. The course of milk stasis was of short duration and the outcome was good independent of treatment. In cases of noninfectious inflammation the symptoms persisted for several days without treatment, and half of the patients developed infectious mastitis. Emptying of the breast resulted in a significant decrease in the duration of symptoms and a significantly improved outcome. Infectious mastitis without treatment was followed by a good result in only 15% of the cases, and 11% developed abscesses. Emptying of the breast increased the rate of a good outcome to 50% and significantly decreased the duration of symptoms. The addition of antibiotic therapy resulted in a good outcome in 96% of the cases and a further significant reduction of the persistence of symptoms.