Histopathologic spectrum of vaginal adenosis and related changes in stilbestrol-exposed females

A total of 98 colposcopically directed biopsies were obtained from the vagina, cervix, and cervicovaginal ridge (hood) of 80 young women believed to have had intrauterine exposure to stilbestrol (DES). Specific investigation of the patient's medical records corroborated the history of maternal stilbestrol administration in 36 patients (45%), while in the remainder the drug history was regarded as presumptive since medical records were unavailable for review. The findings did not differ significantly in those biopsies taken from patients with confirmed or presumptive drug histories. Histologic evidence of vaginal adenosis was detected in vaginal biopsies from 43 patients. In 30 cases (70%) benign Müllerian-type glandular epithelium was in the superficial vaginal wall, residing on the mucosal surface and/or in the lamina propria. The glandular epithelium predominantly was of endocervical type, but in six instances it resembled endometrial or fallopian tubal epithelium. The glands were accompanied by varying degrees of squamous metaplasia in 22 cases. When extensive the metaplasia produced transformation zones similar to those seen in the normal cervix. Vaginal biopsies of adenosis from the other 13 patients (30%) revealed squamous metaplasia without demonstrable glands due to complete transformation of all antecedent glandular epithelium by squamous metaplasia. Our studies indicate that squamous metaplasia is a component of major importance in the natural history of adenosis and that the concept of adenosis should be broadened to include those examples comprised exclusively of metaplastic epithelium. In such examples metaplasia is identified by the immaturity and poor glycogenation of the squamous cells and their accompanying squamous pegs which often contain residual gland openings or squamous "eddies." Similar findings were present in biopsies of seven cervicovaginal ridges and in cervical biopsies from 37 patients, except for the absence of endometrial or tubal type glands in the latter site. Although no adenocarcinomas were detected, six patients had squamous dysplasia of the vagina and/or cervix. In no case were premalignant or dysplastic changes of glandular cells found. Our findings support the thesis that stilbestrol-associated adenosis represents anomalous embryologic localization of the original squamocolumnar junction in the vagina rather than in the cervix. It is closely related to so-called cervical "erosions." The development of squamous metaplasia accounts for modifications in the clinical and histologic appearances by producing transformation zones which then may be subject to the same oncogenic stimuli for squamous neoplasia as are their counterparts in the cervix.     

Incidence and pathophysiological changes in chronic two-kidney hypertension in the dog

Unilateral renal artery plication in dogs reduced renal blood flow by 80% and produced a sustained elevation in arterial pressure whereas plasma renin activity increased for only 4 days. Sodium was retained for 3 days after plication, but this response is similar to that after a sham operation. Of seven dogs studied chronically, elevated arterial pressure was sustained for 27 days or longer in six animals. In three dogs hypertension continued for 2 mo before collateral vessels developed and arterial pressure fell; ligation of these collaterals restored hypertension. Arterial pressure was unaffected by an infusion of [1-sarcosine, 8-alanine] angiotensin II in chronic hypertensive dogs on a normal sodium intake. This angiotensin antagonist lowered arterial pressure after sodium depletion, but became ineffective following rapid sodium repletion. Chronic hypertensive dogs showed normal responses to deoxycorticosterone acetate. These findings suggest that the renin-angiotensin system is not critically involved in maintenace of chronic two-kidney renovascular hypertension in the dog. The data also show that the homeostatic role played by the renin-angiotensin system in the maintenance of arterial pressure remained intact in chronic hypertension.     

Alterations of normal left ventricular performance by general anesthesia

Serial invasive and noninvasive (systolic time interval) measurements of left ventricular performance were obtained in six healthy volunteers during general anesthesia employing the following sequence: thiopental induction, succinylcholine (prior to endotracheal intubation), and halothane--100 per cent oxygen at 1.25 and 1.75 MAC. Heart rate (HR), mean pulmonary arterial "wedge" pressure (PAW) and mean systemic arterial pressure (MAP) were measured continuously; cardiac index and systolic time intervals (STI's) were measured during each intervention. At both levels of halothane, MAP and stroke work index decreased (both P less than 0.02), while HR and systemic vascular resistance did not change. At 1.25 MAC halothane PAW was unchanged, but at 1.75 MAC PAW increased from 8 +/- 4 (SD) to 11 +/- 5 torr (P less than 0.02). Preload was altered at 1.25 MAC by administration of 600-1,000 ml lactated Ringer's solution; PAW increased from 9 +/- 4 to 17 +/- 3 torr (P less than 0.01). At 1.75 MAC halothane, volume expansion increased PAW in a similar manner, but the resultant ventricular function curve was depressed compared with 1.25 MAC halothane. In additon, at each level of halothane anesthesia, the ventricular function curve was depressed compared with results obtained in awake normal subjects. Afterload was altered at 1.25 MAC halothane by infusion of phenylephrine sufficient to raise MAP by 30 per cent. This intervention resulted in a greater depression of cardiac performance than that observed at 1.75 MAC halothane alone. Although alterations in STI's were directionally similar to changes observed in invasive hemodynamic measurements, STI's were sensitive to acute alternations in loading conditions. It is concluded that the levels of halothane commonly employed for general anesthesia significantly depress left ventricular performance in normal subjects, as evidenced by abnormal responses to alterations in preload and afterload, and that STI's should not be employed for routine measurement of left ventricular performance during anesthesia unless both the afterload and the preload on the myocardium are known.     

Atrial natriuretic peptide and bradykinin interaction on norepinephrine uptake in rat adrenal medulla

Interactions between atrial natriuretic peptide (ANP) and bradykinin (BDK) on norepinephrine (NE) uptake were demonstrated in the adrenal medulla of the rat. One hundred nM ANP and 10 nM BDK increased total NE uptake. Subthreshold concentration of ANP (1nM) or BDK (1nM) reverted the effects of thre shold concentrations of both peptides (10 nM BDK and 100 nM ANP respectively). Effective concentrations of ANP and BDK acting simultaneously did not induce additive effects on total NE uptake. Threshold concentrations of both peptides increased neuronal NE uptake only. These results suggest interactions between ANP and BDK at the neuronal uptake level. They confirm that ANP and BDK take part in the regulation of the sympathetic activity in the adrenal medulla of the rat.     

Identification of an orally active, nonpeptidyl oxytocin antagonist

L-366,509, a member of a novel class of nonpeptidyl compounds, has been characterized as an orally active oxytocin (OT) antagonist. L-366,509 exhibits a moderate binding affinity (K(i) values, 370-780 nM) for the rat, rhesus and human uterine OT receptor. L-366,509 also binds to vasopressin receptor subtypes (arginine vasopressin-V1 and V2) with measurable affinity in rat (K(i) values, 25-30 microM) and primate (K(i) values, 2-6 microM) tissues. In rat uterine slices, L-366,509 inhibits (IC50 = 1.6 microM) the stimulation of phosphatidylinositol turnover induced by OT but not bradykinin. In the rat isolated uterus, L-366,509 is a competitive and reversible OT antagonist (pA2 = 7.32). In vivo, L-366,509 given i.v. (10 mg/kg) or intraduodenally (10-50 mg/kg) to rats causes a marked and long-lasting inhibition of OT-stimulated uterine activity. OT antagonist activity in a pregnant rhesus macaque (approximately day 135 gestation) is also observed with L-366,509 after i.v. or p.o. dosing. L-366,509 represents a prototype for a new chemical class of OT antagonists with significant p.o. bioavailability.     

A rapid and efficient method for the radiosynthesis and purification of [125I]SCH23982

The radiosynthesis of (1R)-(+)-1-phenyl-3-methyl-7-[125I]iodo-8-hydroxy- 2,3,4,5-tetrahydro-1H-3-benzazepine (commonly referred to as SCH23982) and its use as a high affinity D1 dopamine antagonist ligand have been reported previously. We now provide a simple and inexpensive protocol for the rapid and efficient synthesis of this radioligand based on the Cloramine-T-catalyzed reaction between the commercially available precursor (R)-(+)-1-phenyl-3-methyl- 8-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine and carrier-free sodium [125I]iodide. [125I]SCH23982 is separated rapidly (within 20 min) from the precursor and reaction byproducts (e.g., chlorinated precursor, SCH23390) by reverse-phase HPLC on a C-8 column. The major iodinated product has been identified as SCH23982 based on co-chromatography with authentic SCH23982, UV spectral characteristics, and biological activity. The chromatographic effluent containing the active product is adsorbed on a C-18 Sep-Pak cartridge to remove mobile-phase constituents and permit it to be eluted and diluted to the desired concentration; this technique is used also for periodic repurification. Our synthesis protocol results in final purified product that incorporates ca. 50% of the initial 125I (tested using starting quantities of 1-10 mCi Na125I); the final product has a specific activity of ca. 2500 +/- 350 Ci/mmol. Data from in vitro receptor autoradiographic and homogenate studies with this radioligand are consistent with previously reported values in terms of expected receptor distribution, affinity, and density (KD of 1.0 nM, Bmax of 1400 fmol/mg protein in rat striatal membranes).     

Efficacy of a standard human anthrax vaccine against Bacillus anthracis spore challenge in guinea-pigs

The efficacy of an anthrax vaccine licensed for human use, MDPH-PA, was tested in guinea-pigs intramuscularly challenged with 10, 100 or 1000 LD50 of spores from two virulent strains of Bacillus anthracis, Vollum 1B and Ames. As demonstrated in other investigations, immunization with MDPH-PA provided better protection against challenge with the Vollum 1B strain than with the Ames strain, although vaccine efficacy against the Ames strain was better than previously reported. Enzyme-linked immunosorbent assay of serum antibody titres to B. anthracis protective antigen showed that there was no significant correlation between survival and antibody titres.     

Conversion of cortisol to cortisone by the human uterus and its reversal in pregnancy

Inter-conversion of cortisol (F) and cortisone (E) was investigated by incubating minced tissue with tritiated cortisol or cortisone and then separating the products by Sephadex LH-20 column chromatography. In non-pregnant subjects conversion of F to E predominated (43.4+/-3.4% vs 0.1+/-0.4% for E to F). In early pregnancy F leads to E decreased and E leads to F rose while at term E leads to F (46.3+/-9.1%) exceeded F leads to E (15.1+/-6.8%). These results were in accord with those obtained by assaying the endogenous concentrations. In non-pregnant subjects the F/E ratio (1.1+/-0.6) was lower than that found in serum (6.3+/-2.2) while at term the uterine F/E (9.0+/-1.8) was similar to that of serum (8.8+/-2.0). These changes resulted in an 8-fold increase in uterine F compared with a 3-fold increase in serum F, while uterine E fell to 1/2 and serum E doubled. Thus, during pregnancy there is a dramatic reversal of the reaction in the uterus in favour of the active hormone. It seems possible that the increase in cortisol thus brought about may play an anti-immune role in uterine wall, the single tissue apart from blood in direct contact with fetal tissue.     

Circulatory disturbances following transient soft tissue compression trauma

Circulatory changes following standardized compression trauma to the hind leg in dogs were evaluated using an electromagnetic flow meter and repeated angiography. A transient increase of flow to the injured limb and within the traumatized region was observed. Good agreement was found between the electromagnetic flow recordings and estimates of relative changes in flow by the angiographic method.