Hemorrhage During Long-Term Anticoagulant Drug Therapy—Part I: Intracranial Hemorrhage

Intracranial hemorrhage was the most serious hemorrhage as measured by death and disability, occurring during long-term anticoagulant drug therapy of 1,626 patients. Among 95 hemorrhagic episodes considered life-threatening or potentially crippling, 30 were intracranial and 56 were gastrointestinal. Over two-thirds of the patients with intracranial hemorrhage died, as against one-tenth of those with gastrointestinal hemorrhage.The incidence of intracranial hemorrhage is increased among hypertensive patients, but the results of a controlled study indicate that the incidence of intracranial hemorrhage is not affected by whether or not the hypertensive patient is receiving anticoagulant therapy. Hypertension is the important precipitating factor, not the prothrombin level. Even at excessively low prothrombin levels only one intracranial hemorrhage occurred in 337 instances.In this series, reducing coagulability to a desirable range did not increase the probability of intracranial hemorrhage. Once bleeding occurred, however, it increased the risk of death and disability.     

Reproductive systems of the North Indian langur (Presbytis entellus entellus Dufresne)

The gross anatomy and histology of the gonads and accessory sex organs are described for male and female Presbytis e. entellus. The langur differs from other catarrhine monkeys in certain specialised characters. The “sexual skin” is not comparable to the true sexual skin of the Cercopithecinae which exhibits cyclical change during the various phases of reproduction; it is nevertheless fully developed in the adult male and serves as one of the secondary sexual characters. Certain aspects of the reproductive system strikingly resemble those of man. The combined testicular weight (0.07% body weight) is similar to the human (0.08%), and the male has ampullary glands. The cervical canal is straight like that of a baboon or man. The corpus luteum (except in the lactating female) is a hollow glandular structure. Extensive hemorrhage which always accompanies ovulation in the langur, does not appear to be a common phenomenon in any other catarrhine for which ovulation and the development of corpus luteum have been studied. The hemorrhagic remains are retained for a long time in the ovulated follicle. The ovary is characteristically large and averages 0.74 gm without corpus luteum and 1.57 gm with corpus luteum, a feature never reported in any other catarrhine monkeys. The pre-ovulatory follicle may attain a size of 14 × 14 mm.     

超声在诊断卵巢黄体破裂中的应用

目的探讨超声对卵巢黄体破裂的诊断价值。方法回顾性分析35例经超声诊断卵巢黄体破裂的声像特点及临床表现。结果35例均有不同程度的腹盆腔积液。24例手术治疗并病理证实,11例保守治疗,超声表现为盆腔积液,卵巢囊肿,附件区包块。结论超声对卵巢黄体破裂的早期快速诊断和制定治疗方案及愈后,有及其重要价值和意义。     

Detection of unsuspected ovarian pregnancy by wedge resection

Five follicular ovarian implantations occurred among 200 ectopic pregnancies encountered during a 14-year period. Abortions from impregnated follicles may cause hemoperitoneum more often than is generally suspected. Wedge resection or cystectomy to ensure hemostasis provides tissue for histological examination, without which ruptured ovarian pregnancy may masquerade as rupture of a corpus luteum with hemorrhage (“ovarian apoplexy”). Including patients reported here, IUCD users have within the past five years accounted for about 10% of all ovarian pregnancies recorded in English.     

Neurosurgical complications of anticoagulant therapy

Ten cases of subdural hematoma and one case of spinal epidural hematoma encountered in patients who were receiving anticoagulant therapy are discussed.This surprisingly large number of complications was observed within three years in a single hospital and represents 36.6% of all chronic and subacute subdural hematomas seen during the same period. The cases are analyzed and the conclusion reached that the causal relationship between anticoagulant therapy and hemorrhage cannot be denied.Suggestions are made as to how to decrease the danger of such complications.     

Expression of the beta-chain of the complement regulator C4b-binding protein in human ovary.

Human C4b-binding protein (C4BP) is an important regulator of the complement system that also binds and inactivates the anticoagulant vitamin K-dependent protein S. These two activities are performed by two distinct polypeptides of 70 kDa and 45 kDa known as alpha and beta chains, respectively. C4BP is present in plasma in various isoforms with different alpha/beta composition. We report here that C4BPbeta, but not C4BPalpha, is expressed in adult human ovary. Expression of C4BPbeta was detected in all ovarian biopsies analyzed (n = 15), independently of age and phase of the menstrual cycle. In situ hybridization and immunostaining analyses on cryostat sections demonstrated expression of C4BPbeta in both regressing corpus luteum and corpus albicans, but not in the follicles, the corpus luteum, the ovary stroma or the vascular cells. In addition, we noted that the expression pattern of the C4BPbeta mRNA resembles that described for the connective tissue that invades the degenerating corpus luteum and causes a progressive fibrosis that gradually converts it into a scar, the corpus albicans. RT-PCR and immunostaining analyses of primary cultures derived from human ovaries demonstrated the presence of fibroblast-like cells that express C4BPbeta. As a whole, these data suggest a role for the C4BPbeta in human ovary during the healing and scar resorption processes that leads to the formation of the corpus albicans and its replacement by ovarian stroma.     

Corpus luteum size and plasma progesterone concentration in cows

It is often assumed that a larger corpus luteum will produce more progesterone and generate higher circulating plasma concentrations. The aim of the study was to determine whether the size of the corpus luteum does actually determine circulating plasma progesterone concentrations. Data were collated from a number of studies on various aspects of luteal function in non-lactating dairy cows to allow comparisons to be made between corpus luteum weight and plasma progesterone concentration across the luteal phase. In these studies oestrous cycles had been synchronised and animals slaughtered on day 5, day 8 or day 16 following oestrus. Both corpus luteum weight and plasma progesterone concentration increased between day 5 and day 8. Plasma progesterone concentration but not luteal weight also increased between day 8 and day 16. On day 5 there was a strong relationship between corpus luteum weight and plasma progesterone (R² = 0.64; P < 0.001). However, no such relationship was present on day 8 or day 16. These results indicate that while during the early stage of corpus luteum development a relationship between size and progesterone is present, by day 8 of the cycle, the size of the corpus luteum is no longer of importance in determining circulating progesterone concentrations.     

The size of the corpus luteum during pseudopregnancy and pregnancy in the rat.

The corpus luteum in mature Sprague Dawley rats was weighted at the various stages of pseudopregnancy and pregancy. The average size of these corpora lutea was 1.0 +/- 0.10 mg, 1.61 +/- 0.69 mg, 1.90 +/- 0.25 mg, 3.69 +/- 0.36 mg, and 4.37 +/- 0.50 mg on day 2 of diestrus, on days 10-15 of psuedopregnancy, on days 9-10, 14, and 20 of pregnancy, respectively. The fact that the average size of the corpus luteum on days 10-15 of pseudopregnancy was larger than that on day 2 of diestrus is thought to drive from prolonged exposure of the corpus luteum to prolactin. The average size of the corpus luteum on days 9-10 of pregnancy had a tendency to be larger than that on days 10-15 of pseudopregnancy and this seems to demonstrate that the placenta secreted placental lactogen by this stage of pregnancy. The average size of the corpus luteum on day 14 of pregnancy was larger than that on days 9-10 of pregnancy. This phenomenon might be attributed to the presence of large amounts of placental lactogen secreted from the placenta between days 10 and 14 of pregnancy. Furthermore, it was noted that the size of the corpus luteum on day 20 of pregnancy was larger than that of day 14, which suggests that further secretion of placental lactogen continued after day 14 of pregnancy. As there was a remarkable decrease in the number of fetuses on day 20 of pregnancy when overiectomy was performed on day 14 of pregnancy, the ovary was considered indispensable in maintaining pregnancy in the rat.     

Identification and physical mapping of genes expressed in the corpus luteum in cattle

A representational difference analysis was performed to identify genes expressed in the corpus luteum of cattle. The corpus luteum is an ovarian structure that is essential for the establishment and maintenance of pregnancy. Knowledge of gene expression and function of corpus luteum will be important to improve fertility in humans and domestic animals. Housekeeping genes were removed from the corpus luteum representation (tester) using skeletal muscle as the subtracting agent (driver). A total of 80 clones of the final subtraction product were analysed by sequencing and 11 new bovine gene sequences were identified (pBTCL1-11). The sequences were mapped to segments of 10 different chromosomes using a somatic cell hybrid panel and a radiation hybrid panel. With one exception the locations are in agreement with published comparative maps of cattle and man. Expression in corpus luteum was verified by RT-PCR for all the 11 clones.     

Morphogenesis and histophysiology of the corpus luteum

A great amount of different problems on morphogenesis and histophysiology of the corpus luteum is presented, with an emphasis on light optic and ultrastructural data that characterize the developmental dynamics of the corpus luteum. The vascular reaction is described in details, beginning from the preovulatory period. The total high vascularization rate is demonstrated and certain information on ultrastructure of newly formed capillaries and macrophages is concerned with. For the first time the authors' data on intravascular macrophages are given. The role of macrophages in the function and structural dynamics of the corpus luteum is discussed. Owing to the results obtained histochemically, ultrastructurally and biochemically, the subject on dynamics of the corpus luteum hormonoproduction, on processes participating in the hormone secretion, as well as on the role of the interstitial tissue in the corpus luteum formation is considered. The data from the literature and those of the authors are presented concerning the means and ways of progesteron transport in the form of vesicles, granules, or by means of molecular diffusion. Participation of the corpus luteum macrophages (tissue and vascular ones) in processes of synthesis and transport of progesteron is analysed. The role of prostaglandins in the chain of regulation of development, function and involution of the corpus luteum is studied. The changes in balance of prostaglandins, when prostaglandin F2 is administered result in decreasing amount of progesterone in blood. In the experiment, synthesis of prostaglandins is blocked by indometacin administration and it causes certain disturbances in luteal transformation.     

Plasma androgens during the luteal phase in a case of true hermaphroditism with bilateral ovotestis

A true hermaphrodite with a bilateral ovotestis and a 46 XX karyotype was studied. This 14-year old subject developed ambiguous puberty with bilateral gynecomastia and stage IV public hair. Relatively high level of testosterone (T) (2.80 ng/ml), was found. The 5 alpha-reductase activity for T in the pubic skin was similar to that observed in normal adult males. A hemorrhagic corpus luteum in the left ovotestis was observed at laparotomy. The luteal phase immediately after dexamethasone administration (1 mg/day for 7 days) was characterized by a significant decrease of plasma androgens, T and androstenedione (A). The constantly low level of T (0.30 ng/ml) during the luteal phase in this subject did not appear to be due to the previously administered dexamethasone. This decrease of T production in the luteal phase might be secondary either to the increase of the estradiol-17 beta (E2) secreted by the corpus luteum or to the decrease of LH levels. Both mechanisms might act concomitantly.     

Microvascular endothelial cells of the corpus luteum

The cyclic nature of the capillary bed in the corpus luteum offers a unique experimental model to examine the life cycle of endothelial cells, involving discrete physiologically regulated steps of angiogenesis, blood vessel maturation and blood vessel regression. The granulosa cells and theca cells of the developing antral follicle and the steroidogenic cells of the corpus luteum produce and respond to angiogenic factors and vasoactive peptides. Following ovulation the neovascularization during the early stages of corpus luteum development has been compared to the rapid angiogenesis observed during tumor formation. On the other end of the spectrum, the microvascular endothelial cells are the first cells to undergo apoptosis at the onset of corpus luteum regression. Important insights on the morphology and function of luteal endothelial cells have been gained from a combination of in vitro and in vivo studies on endothelial cells. Endothelial cells communicate with cells comprising the functional unit of the corpus luteum, i.e., other vascular cells, steroidogenic cells, and immune cells. This review is designed to provide an overview of the types of endothelial cells present in the corpus luteum and their involvement in corpus luteum development and regression. Available evidence indicates that microvascular endothelial cells of the corpus luteum are not alike, and may differ during the process of angiogenesis and angioregression. The contributions of vasoactive peptides generated by the luteal endothelin-1 and the renin-angiotensin systems are discussed in context with the function of endothelial cells during corpus luteum formation and regression. The ability of two cytokines, tumor necrosis factor alpha and interferon gamma, are evaluated as paracrine mediators of endothelial cell function during angioregression. Finally, chemokines are discussed as a vital endothelial cell secretory products that contribute to the recruitment of eosinophils and macrophages. The review highlights areas for future investigation of ovarian microvascular endothelial cells. The potential clinical applications of research directed on corpus luteum endothelial cells are intriguing considering reproductive processes in which vascular dysfunctions may play a role such as ovarian failure, polycystic ovary syndrome (PCOS), and ovarian hyperstimulation syndrome (OHSS).     

HIF-1在卵巢黄体发育过程中对血管新生的调控作用

在哺乳动物中,卵巢黄体（corpus luteum,CL）是由破裂排卵后的卵泡所形成的,也是血管增生比较激烈的地方。尤其是在卵巢黄体早期发育阶段,这种快速形成的致密毛细血管网可以确保产生激素的细胞获得氧气、营养和合成激素等所必要的前体,同时释放大量的激素用于早期妊娠的建立和维持。目前的研究已经表明,血管内皮生长因子（vascular endothel ial growth factor,VEGF）作为重要的促血管生成因子,在卵巢黄体发育过程中对血管增生具有至关重要的调节作用,而VEGF作为转录因子HIF－1的下游靶基因,受缺氧诱导因子HIF－1信号通路的调控。该文一方面对卵巢黄体发育过程中VEGF依赖性血管增生的调控机制进行概述,另一方面就转录因子H1F－1对VEGF的转录激活调控机制进行系统阐述,从而揭示HIF－1对卵巢黄体发育过程dgVEGF依赖性血管新生的调控作用,为进一步研究哺乳动物卵巢黄体发育过程中血管增生的分子调控机制提供坚实的理论基础。     

Modeling Intracerebral Hemorrhage Growth and Response to Anticoagulation

The mechanism for hemorrhage enlargement in the brain, a key determinant of patient outcome following hemorrhagic stroke, is unknown. We performed computer-based stochastic simulation of one proposed mechanism, in which hemorrhages grow in “domino” fashion via secondary shearing of neighboring vessel segments. Hemorrhages were simulated by creating an initial site of primary bleeding and an associated risk of secondary rupture at adjacent sites that decayed over time. Under particular combinations of parameters for likelihood of secondary rupture and time-dependent decay, a subset of lesions expanded, creating a bimodal distribution of microbleeds and macrobleeds. Systematic variation of the model to simulate anticoagulation yielded increases in both macrobleed occurrence (26.9%, 53.2%, and 70.0% of all hemorrhagic events under conditions simulating no, low-level, and high-level anticoagulation) and final hemorrhage size (median volumes 111, 276, and 412 under the same three conditions), consistent with data from patients with anticoagulant-related brain hemorrhages. Reversal from simulated high-level anticoagulation to normal coagulation was able to reduce final hemorrhage size only if applied relatively early in the course of hemorrhage expansion. These findings suggest that a model based on a secondary shearing mechanism can account for some of the clinically observed properties of intracerebral hemorrhage, including the bimodal distribution of volumes and the enhanced hemorrhage growth seen with anticoagulation. Future iterations of this model may be useful for elucidating the effects of hemorrhage growth of factors related to secondary shearing (such as small vessel pathology) or time-dependent decay (such as hemostatic agents).     

The effects of GnRH treatment at the time of AI and 12 days later on reproductive performance of high producing dairy cows during the warm season in northeastern Spain

It was hypothesized that gonadotropin-releasing hormone (GnRH) treatment at the time of insemination and 12 days later increases conception rates. The aim of the present study was to evaluate the effects of GnRH treatment at the time of insemination or at the time of insemination and 12 days later on reproductive performance during the warm season in high producing dairy cows. The effect of GnRH treatment on the incidence of subsequent twin pregnancies and pregnancy losses was also evaluated. Data were analyzed using logistic regression methods. Of the entire series of 1289 AI, 373 (29%) resulted in pregnancy. Three study groups were established to evaluate the effects of treatment on the conception rate: control (untreated cows, n=431), GnRH-0 (cows receiving GnRH at AI, n=429) or GnRH-0+12 (cows receiving GnRH at AI and at AI+12 days, n=429). Conception rates were 20.6% (89/431), 30.8% (132/429) and 35.4% (152/429) for animals receiving no treatment, GnRH at AI, and GnRH at AI and 12 days later, respectively. Based on the odds ratio, the probability of pregnancy was 0.80 and 0.46 times less likely for cows receiving treatment GnRH-0 and no treatment, respectively, than for cows receiving treatment GnRH-0+12 (reference). Of the 373 pregnant animals, 326 (87.4%) bore singletons and 47 (12.6%) carried twins. The effects of treatment on the dependent variables: twin pregnancy, additional corpus luteum and pregnancy loss were analyzed. Pregnancy loss between 38 and 90 days after insemination was registered in 30 (8%) cows: 17 (5.2%) in single and 13 (27.7%) in twin pregnancies. Fifty-six (15%) cows had an additional corpus luteum. No pregnancy losses were recorded in these cows. Treatment had no effect on the twin pregnancy rate. The treatment GnRH at AI and 12 days later increased the chances of an additional corpus luteum by a factor 3.7 (using the control group as reference). In conclusion, our results support the hypothesis that GnRH treatment at the time of insemination and 12 days later increases the conception rate in high producing dairy cows during the warm season. Although lower than double treatment, strong benefits were also registered following a single GnRH treatment at insemination. Under these conditions, treatment fails to affect the twin pregnancy rate yet increases the incidence of an additional corpus luteum in pregnant cows.     

Megakaryocytes in a hemorrhagic pleural effusion caused by anticoagulant overdose

Sudden widespread hemorrhage, including a hemorrhagic pleural effusion, developed in a patient due to an overdose of anticoagulant. The pleural fluid contained megakaryocytes. Necropsy did not reveal myeloid metaplasia or any myeloproliferative disorder. Since megakaryocytes are normally found in pulmonary parenchyma, their presence in the pleural fluid was attributed to the hemorrhagic condition of the lung, which enabled megakaryocyte-containing blood to enter the pleural cavity.     

Aspects of reproduction in female Ross seals (Ommatophoca rossii)

Ovaries were collected from 26 Ross seals shot in the King Haakon VII Sea south of the 60 degrees latitude during 3 periods, between 12 January and 2 February 1980-1982. The structure of the ovaries resembled that of other pinnipeds. A corpus luteum was found in 18 of 26 females, which therefore were regarded as reproductive. However, no females were lactating or visibly pregnant (presence of fetus in the uterus). Of the remaining 8 females (non-reproductive), 3 had neither a corpus luteum nor a corpus albicans. Ovulation did not alternate between ovaries in 4 of 10 females. Ovarian weight was greater in reproductive females than in non-reproductive females, and was also correlated with presence of a corpus luteum. Follicular development was more advanced in reproductive females than in non-reproductive females, and it was also more pronounced in the ovary containing a corpus luteum. The finding of a high percentage of females with a corpus luteum, but with no fetus in the uterus, together with histological characteristics of the ovarian structures in the present study, and earlier published data on mating, pupping and moulting, provide circumstantial evidence for delayed implantation in Ross seals.     

Androgen synthesis and aromatization by equine corpus luteum microsomes

Whereas mare corpus luteum does not produce androgens or estrogens in vivo, the incubation of mare corpus luteum microsomes with progesterone and NADPH resulted in 17 alpha-hydroxyprogesterone and estrogen production with a small yield of androstenedione. In the presence of an aromatase inhibitor (4-hydroxyandrostenedione), 17 alpha-hydroxyprogesterone and androstenedione were accumulated. Aromatization of testosterone and androstenedione occurred via stereospecific loss of the 1 beta, 2 beta hydrogen atoms and was inhibited by MgCl2, KCl, and EDTA. The Km of estrogen synthetase from equine corpus luteum for testosterone was 18.5 +/- 2.7 nM and for androstenedione was 11.5 +/- 1.5 nM. 19-Norandrogens were aromatized with a slightly higher efficiency than were androgens, but the affinity of the aromatase was lower for 19-norandrogens than for androgens. Our results suggest that aromatases from equine testis and corpus luteum are closely related enzymes. On the other hand, the question arises as to the relationship among the cell origin, the synthetizing abilities, and in vivo production of the corpus luteum in different mammalian species.     

Physiological and immunocytochemical evidence for a new concept of blood flow regulation in the corpus luteum

To explain the high rate of blood flow in the corpus luteum, we hypothesize that luteal blood vessels offer minimal resistance to flow and are incapable of vasomotion. This hypothesis was tested in rabbits at mid-pseudopregnancy by measuring blood flow in the corpus luteum and ovarian stroma with tracer-labeled microspheres at three levels of arterial blood pressure, which was manipulated by constricting the aorta above the ovarian artery. In addition, the distribution of vascular smooth muscle in the ovary was evaluated with morphological and immunocytochemical techniques. Decreases in arterial pressure were paralleled by reductions in blood flow in the corpus luteum, whereas ovarian stromal blood flow was unchanged. Consistent with our hypothesis, there was no change in the low level of vascular resistance offered by blood vessels in the corpus luteum, supporting the view that they are maximally dilated and incapable of autoregulation. Morphologically, the vessels within the corpus luteum appeared as large sinusoidal capillaries without smooth muscle, providing an anatomical explanation for the lack of vasomotor control demonstrated physiologically. The absence of vascular smooth muscle was confirmed with immunocytochemistry using an antibody against the muscle-specific intermediate filament, desmin. The fluorescein-labeled antibody decorated arteries and arterioles within the ovarian stroma and near the capsule of the corpus luteum, but did not decorate vessels in the corpus luteum of pseudopregnancy, providing additional evidence that the vessels of the corpus luteum lack the smooth muscle investment necessary to change vascular caliber. From these findings, we have proposed a novel scheme to explain intraovarian blood flow regulation. Vascular resistance in the ovarian stroma, as in most tissues, is acutely regulated by dilation or constriction of intratissue arterioles. In contrast, vascular resistance within the corpus luteum is modeled as a relatively invariable parameter, fixed at a low level by the morphological characteristics of the luteal vasculature. Therefore, the corpus luteum operates on a linear (maximally "vasodilated") pressure-flow curve, does not actively regulate intratissue blood flow, and is subject to acute regulation of perfusion only through changes in extra-luteal vessels.     

Platelet-derived growth factors and receptors in the rat corpus luteum: localization and identification of an effect on luteogenesis

Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) play a vital role in regulating cell growth and angiogenesis. In this study, the expression of the family of PDGFs and PDGFRs in the ovarian corpus luteum were identified and characterized, and an effect of their activity on development of the corpus luteum revealed. Gonadotropin-stimulated immature rats were utilized as a model of induced ovulation, luteogenesis, and pseudopregnancy. Levels of ovarian mRNA for Pdgfb and Pdgfd, and their receptor, Pdgfrb, increased significantly as early as 4 h after human chorionic gonadotropin (hCG) injection in immature rats primed with equine chorionic gonadotropin (eCG). Gonadotropin regulation of Pdgfb expression was confirmed by in vitro promoter-reporter assays, which showed a 2- to 3-fold increase in Pdgfb promoter activity in response to luteinizing hormone (LH). Inhibition studies implicated protein kinase A, phosphatidylinositol 3-kinase and mitogen activated protein kinase signaling pathways in the LH-induced upregulation. In the corpus luteum, PDGFA, PDGFB, PDGFC, and PDGFRA were localized to a population of luteal parenchymal/steroidogenic cells. PDGFRB was expressed primarily in what appeared to be cells of the luteal microvasculature. Intraovarian injection of an inhibitor of PDGF receptor activity, the tyrphostin AG1295, prior to injection of hCG in eCG-primed immature rats resulted in a significant 21.86%+/-11.15% decrease in corpora lutea per treated ovary in comparison to the contralateral vehicle-injected control ovary. In addition, the treated ovary of 3 of 16 rats showed widespread hemorrhage throughout the entire ovary, indicating a possible role for PDGF receptor activity in maintenance of the ovarian vasculature.