Marked improvement in the success rate of medical management of early pregnancy failure following the implementation of a novel institutional protocol and treatment guidelines: a follow-up study.

PURPOSE: To analyze the success rate, time to passage of tissue and subjective patient experience of a newly implemented protocol for medical management of early pregnancy failure (EPF) over a 2-year period. METHODS: A retrospective chart review of all patients with early pregnancy failure primarily opting for medical management was performed. 200 mg mifepristone were administered orally, followed by a single vaginal dose of 800 mcg misoprostol after 36-48 h. We followed-up with our patients using a written questionnaire. RESULTS: 167 women were included in the present study. We observed an overall success rate of 92 %, defined as no need for surgical management after medication administration. We could not identify predictive values for success in a multivariate regression analysis. Most patients (84 %) passed tissue within 6 h after misoprostol administration. The protocol was well tolerated with a low incidence of side effects. Pain was managed well with sufficient analgesics. Responders to the questionnaire felt adequately informed prior to treatment and rated their overall experience as positive. CONCLUSION: The adaption of the institutional medical protocol resulted in a marked improvement of success rate when compared to the previously used protocol (92 vs. 61 %). We credit this increase to the adjusted medication schema as well as to targeted physician education on the expected course and interpretation of outcome measures. Our results underscore that the medical management of EPF is a safe and effective alternative to surgical evacuation in the clinical setting.

Female fertility loss and preservation: threats and opportunities.

BACKGROUND: Ovarian aging and cytotoxic treatments are the most common causes for fertility loss in women. With increasing numbers of young female survivors following cytotoxic cancer treatments, the issue of fertility preservation has assumed greater importance. METHODS: We review the literature on the causes of female fertility loss as well as the recent advances in fertility preservation options and strategies that might be of interest to oncologists. Currently, several methods and techniques exist for fertility preservation of female patients with cancer including embryo freezing, ovarian protection techniques, oocyte cryopreservation, ovarian tissue cryopreservation followed by autotransplantation, and recently in vitro culture of ovarian tissue, follicles, and oocytes. Each method or technique has advantages and disadvantages related to current success rate, required delay in cancer treatment, sperm requirement, and risk of reintroducing cancer cells. RESULTS: To date, embryo freezing is the only established method successfully and widely used for fertility preservation of female patients with cancer. The other methods are promising but still considered experimental. CONCLUSION: Patient awareness, physician knowledge, early counseling, costs management, international registry, interdisciplinary networks, and research development are necessary to improve the current care in the field of female fertility preservation.

Ultrasonographic assessment of skin thickness in patients with PCOS - a case-control study.

OBJECTIVE: To measure skin thickness in patients with polycystic ovary syndrome (PCOS) in comparison to controls and to examine a possible association with sex steroids, body mass index, lipid profile and hyperinsulinemia. METHODS: Thirty patients with confirmed PCOS were compared to thirty-two women presenting for infertility workup. Skin thickness was measured using high-resolution ultrasound in a standardized area, blood samples were collected once at presentation. RESULTS: Patients with PCOS showed a statistically significant thicker skin than women in the control group (0.95 mm (±0.093 mm) versus 0.85 mm (±0.077 mm, p < 0.0001)). LH, estradiol, testosterone, the free androgen index, triglycerides, cholesterol, LDL-cholesterol and body mass index were significantly increased in PCOS - patients. No correlation between hyperinsulinemia and skin thickness was seen. CONCLUSIONS: PCOS - patients showed a greater skin thickness in comparison to women without PCOS. This might be due to proliferative effects of sex steroids such as estrogens and testosterone and metabolic derangements on skin thickness.

Impaired body image in patients with multiple sclerosis.

OBJECTIVE: Despite the growing research on body image disturbances in chronically ill patients, reports of such disturbances in patients with multiple sclerosis (MS) are scarce. The aim of this study was to assess the occurrence of different aspects of body image disturbances in patients with MS, taking into account the disability status as well as depressive symptoms. MATERIALS & METHODS: Forty patients with MS and 28 healthy controls were investigated with questionnaires assessing attractiveness/self-confidence, accentuation of external appearance, worries about possible physical deficits, sexual problems, vitality and depressive symptoms. In MS patients, medical parameters like the expanded disability status were assessed too. RESULTS: In comparison with healthy controls, the MS patients, being although only mildly disabled and in a quite stable mood, reported significantly higher worries about physical deficits, described a significantly worse body appraisal and significantly more sexual problems. While female MS patients predominantly suffered from worries concerning physical deficits and feelings of being less attractive, sexual problems were of particular concern in male MS patients. CONCLUSIONS: Even mildly impaired MS patients who are not markedly depressed have to deal with problems of body image. Improvement of body image perception in MS patients taking gender-specific differences into account represents a promising area of future psychological research.

Quantitative correlation between the void morphology of niobium-tin wires and their irreversible critical current degradation upon mechanical loading.

Understanding the critical current performance variation of Nb3Sn superconducting wires under mechanical loading is a crucial issue for the design of next generation accelerator and fusion magnets. In these applications, the mechanical properties of the conductors may become a limiting factor due to the strong electro-magnetic forces resulting from the combination of large magnets and intense magnetic fields. In particular, the presence of voids in the superconducting filament structure, which are formed during the fabrication and the reaction heat treatment, determines localized stress concentrations and possibly the formation of cracks. In this work, we demonstrate a quantitative correlation between the void morphology and the electro-mechanical limits measured on different Bronze route Nb3Sn wires. Hot Isostatic Pressing (HIP) prior to the reaction heat treatment is utilized to partially eliminate the voids. The wires' void distributions - with and without HIP treatment - are detected and statistically analyzed using high energy X-ray micro tomography. The stress concentration due to the shape and distribution of the voids as well as their impact on the electro-mechanical properties are determined through finite element method modeling. Finally, the results are quantitatively correlated with the experimentally determined limits of the irreversible critical current degradation upon mechanical loading.

Physiology of upward transport in the human female genital tract.

The uterus and fallopian tubes represent a functionally united peristaltic pump under the endocrine control of ipsilateral ovary. We have examined this function by using hysterosalpingoscintigraphy (HSS), recording of intrauterine pressure, electrohysterography, and Doppler sonography of the fallopian tubes. An uptake of labeled particles into the uterus was observed during the follicular and luteal phases of the cycle after application into the vagina. Transport into the oviducts, however, could only be demonstrated during the follicular phase. Furthermore, the predominant transport was into the tube ipsilateral to the ovary containing the dominant follicle. The pregnancy rate following spontaneous intercourse or insemination was higher in those women in whom ipsilateral transport could be demonstrated. The amount of material transported to the ipsilateral tube was increased after oxytocin administration, as demonstrated by radionuclide imaging and by Doppler sonography following instillation of ultrasound contrast medium. An increase in the basal tone and amplitude of contractions was observed after oxytocin administration. These results support the idea that the uterus and fallopian tubes act as a peristaltic pump, which increases transport of sperm into the oviduct ipsilateral to the ovary bearing the dominant follicle. Oxytocin appears to play a critical role in this peristaltic pump. A failure of the peristaltic mechanism is possibly responsible for infertility. We propose the term tubal transport disorder (TTD) as a nosological entity. Results from HSS could be a useful adjunct for choosing treatment modalities in patients with patent fallopian tubes suffering from infertility. These patients may be better served with in vitro fertilization (IVF).

Parameters of the fibrinolytic system in patients undergoing BMT: elevation of PAI-1 in veno-occlusive disease.

Veno-occlusive disease (VOD) represents one of the more frequent and most severe complications after BMT. The pathophysiology of VOD is poorly understood. To investigate a possible link between endothelial cell damage and VOD, tissue plasminogen activator (tPA) and its inhibitor (PAI-1) were measured in 32 patients as endothelial cell-derived parameters of the fibrinolytic system. A nearly fivefold increase (mean 103.9 ng/ml, range 22.6-582.4 ng/ml, p < 0.05) in PAI-1 levels was found in the four patients who developed VOD compared with patients without this complication (mean 22.2 ng/ml, range 1.4-131.6 ng/ml). No significant difference was found in tPA levels between patient groups with or without VOD or other complications following BMT, indicating a shift of the fibrinolytic balance towards hypofibrinolysis particularly in patients with VOD. We conclude that alterations of the fibrinolytic system occur in patients undergoing BMT. Hypofibrinolysis seems to be at least one factor in the pathogenesis of VOD and the determination of PAI-1 might be helpful for diagnosing the disease. Our data also may explain the reported successful treatment of VOD by recombinant tPA.

Towards quantifying cochlear implant localization performance in complex acoustic environments.

Cochlear implant (CI) users frequently report listening difficulties in reverberant and noisy spaces. While it is common to assess speech understanding with implants in background noise, binaural hearing performance has rarely been quantified in the presence of other sources, although the binaural system is a major contributor to the robustness of speech understanding in noisy situations with normal hearing. Here, a pointing task was used to measure horizontal localization ability of a bilateral CI user in quiet and in a continuous diffuse noise interferer at a signal-to-noise ratio of 0 dB. Results were compared to localization performance of six normal hearing listeners. The average localization error of the normal hearing listeners was within normal ranges reported previously and only increased by 1.8° when the interfering noise was introduced. In contrast, the bilateral CI user showed a localization error of 22° in quiet which rose to 31° in noise. This increase was partly due to target sounds being inaudible when presented from frontal locations between -20° and +20°. With the noise present, the implant user was only able to reliably hear target sounds presented from locations well off the median plane. The results give support to the informal complaints raised by CI users and can help to define targets for the design of, e.g., noise reduction algorithms for implant processors.

Leydig-cell-tumor of the ovary that responded to GnRH-analogue administration - case report and review of the literature.

Progressive hirsutism can be a symptom of an androgen-producing tumor, especially in postmenopausal women. We report a case of a 58-year-old woman who complained of progressive hirsutism, nervousness, irritability, anxiousness and an increased libido. Examination showed an unusual redness of her head, décolleté, palms and soles of her feet. Basal laboratory tests revealed a profound elevation of testosterone levels (7.5 microg/l) and normal levels of androstendione, dehydroepiandrosterone-sulfate, 17alpha-hydroxy-progesterone and thyroid-stimulating hormone. Also remarkable was that her red blood count, hemoglobin and hematocrit values were elevated while erythropoietin was within normal limits. Functional laboratory tests ruled out heterozygous C21-hydroxylase deficiency and showed a moderate insulin resistance on the oral glucose tolerance test. Transvaginal ultrasound revealed a slightly hyperdensic area of 6 mm in the left ovary. Magnetic resonance imaging showed a contrast medium-accumulating area of 2 cm in the left ovary. Since the patient was initially reluctant to undergo surgery, a GnRH-analogue (triptoreline) was administered VIA intramuscular injection once per month for two months and testosterone levels were lowered to less than one third of the initial level (2 microg/l). Surgery was eventually performed with laparoscopic bilateral salpingoophorectomy, hysteroscopy and uterine curettage. The histologic examination revealed a Leydig cell tumor in the hilus and stroma of the left ovary. Postoperatively testosterone levels dropped dramatically and instantly into the normal range. Within months, the red blood count and hematocrit levels were within normal limits. The patient's face became more feminine, the redness of her face and hirsutism regressed. Her anxiousness and nervosity resolved and the insulin sensitivity improved. In this paper, polyglobulia, the metabolic and psychological changes due to hyperandrogenism are discussed, as well as the phenomenon that the tumor responded to a GnRH-analogue. Such a response implies that the tumor is either under gonadotropin control or that GnRH analogues have direct effects via receptors on tumorous Leydig cells.

Uterine mechanisms of ipsilateral directed spermatozoa transport: Evidence for a contribution of the utero-ovarian countercurrent system.

OBJECTIVE: Spermatozoa transport into uterus and fallopian tubes is directed to the side of the dominant follicle and seems to be controlled by the ipsilateral ovary. The objective of this study was to evaluate the temperature in the fallopian tubes as well as the concentrations of estradiol and progesterone in the utero-ovarian veins draining the ipsilateral ovary and compare these to the contralateral side of the uterus. STUDY DESIGN: A prospective clinical study. SETTING: Academic-assisted reproductive technology program. SUBJECTS: Temperature was measured in both oviducts of 10 patients each in the early phase as well as during the late follicular phase during the course of examination of tubal patency and function. Blood samples of the ovarian veins were obtained during hysterectomy in 10 premenopausal patients with regular menstrual cycles. Five of the women were in the early follicular phase and 5 were in the late follicular phase. RESULTS: Late follicular phase temperature as well as concentrations of estradiol and progesterone were significantly higher in the ipsilateral tube and the utero-ovarian veins draining the ipsilateral ovary as compared to the contralateral side. No such differences were found during the early follicular phase of the cycle. CONCLUSIONS: These data support our view that the uterus and fallopian tubes during the late follicular phase immediately before ovulation are composed of two functional units with different functional properties acting as a peristaltic pump resulting in increased transport of spermatozoa into the oviduct ipsilateral to the ovary bearing the dominant follicle and that this effect is mediated in part by the utero-ovarian countercurrent system.

[Breast milk studies in the Bitterfeld district]. / Muttermilchuntersuchungen im Landkreis Bitterfeld.

Human milk samples were tested for pesticide residues (particularly chlorinated hydrocarbons) in 1996 in continuation of the environmental medical tests conducted in 1990 and 1993 in Bitterfeld county. Although the overall human milk contamination due to chlorinated hydrocarbons was reduced, there were still higher concentrations of DDT and beta-HCH detected compared to the concentrations found in what was formerly West Germany. The objective of this follow-up testing of 106 human milk samples was to observe overall trends as well as the specific effects of sanitary and environmental protection measures after three years. Sample preparation included fat extraction and chromatographic column studies. The extracts were analyzed by means of two different gas chromatography systems based on electron-catching detectors. Overall, the contamination was reduced compared to the years of 1990 and 1993. Contaminant concentrations did not exceed the "tolerable concentration" while using a safety factor of 10. However, few beta-HCH (2% of the samples), HCB (22%), total DDT (20%), and more than half of total PCB samples exceeded the "tolerable concentrations" while using a safety factor of 100. A major decrease in the average contamination was noticed for total PCB (63% decrease for 0.3 mg/kg of milk fat), beta-HCH (77% decrease for 0.056 mg/kg of milk fat), and HCB (57% decrease for 0.091 mg/kg of milk fat). The concentration of the heptachlorepoxide was even reduced to 1%. Whereas the DDT and DDD concentrations were also reduced compared to 1993 (83% decrease for 0.033 mg/kg of milk fat, and 84% decrease of 0.005 mg/kg of milk fat), the DDE concentration increased (32% increase for 0.755 mg/kg of milk fat). This can be explained by the decomposition of enzymes from DDT to DDE and the extremely high accumulation tendency of this metabolite. The results show that the contamination of women over time was influenced by two contrary factors. On one hand, the internal exposure increases with age; on the other hand lactation eliminates contaminants from the body of the mother. Comparison to other states' data shows that the results match the overall picture of the residue situation in Germany. Results of the environmental-medical investigations from 1996 demonstrate a predominant decrease of contamination with chlorinated hydrocarbons within the human body. This tendency was possibly influenced by two developments. The global usage of persistent chlorinated hydrocarbons was critically observed and regulated more strictly in recent years, which decreased their concentration tremendously. The other reason for the reduction of contamination by chlorinated hydrocarbons in the county of Bitterfeld could be the improving environmental situation in this region.

Cytostatic efficacy of DNA-complexes of adriamycin, daunomycin and actinomycin D. I. Comparative studies in Novikoff hepatoma, human mammary carcinoma cells and human leukemic leukocytes.

Inhibitory effects of adriamycin, daunomycin, actinomycin D and of the related DNA-complexes on DNA and RNA synthesis were compared by precursor uptake studies in Novikoff hepatoma cells, human mammary carcinoma cells and human leukemia cells. In addition, nuclear RNA labelling profiles were analyzed in human acute leukemia blast cells and nucleolar RNA synthesis was studied in Novikoff hepatoma cells in vitro after incubations of the tumor cells with adriamycin and DNA-adriamycin. The studies revealed that compared to the free drugs a) the DNA complexes were generally less active with respect to inhibition of overall DNA and RNA synthesis in these divergent tumor cell types, b) characteristic differences between adriamycin and daunomycin which are related to a more rapid cellular uptake of daunomycin were still present after complexing of both drugs to calf thymus DNA, and c) the intracellular mode of action of the free antibiotics was not changed by complex formation with DNA. These results indicate that a preferential incorporation of the macromolecular complexes into the tumor cells by pinocytosis--as originally postulated by Trouet et al. (1972)--is not likely for Novikoff hepatoma cells, human mammary carcinoma cells and human acute leukemia blast cells. In contrast, it may be concluded from this study that the DNA complexes dissociate already at the outer cell membrane resulting in a generally decreased but kinetically drug-specific cellular uptake. In a second communication it will be demonstrated that these in-vitro effects do not correlate with the therapeutic efficacy efficacy of the complexed drugs in vivo.

Modulation of acute graft-versus-host-disease after allogeneic bone marrow transplantation by tumor necrosis factor alpha (TNF alpha) release in the course of pretransplant conditioning: role of conditioning regimens and prophylactic application of a monoclonal antibody neutralizing human TNF alpha (MAK 195F).

Contribution of host-related cytokine release in the course of pretransplant conditioning to early tissue damage and induction of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT) has been shown in experimental models. We performed a clinical phase I/II trial applying a monoclonal antibody neutralizing human tumor necrosis alpha (TNF alpha) during pretransplant conditioning as additional prophylaxis in high-risk patients admitted to allogeneic BMT; TNF alpha serum levels and clinical courses in 21 patients receiving anti-TNF alpha prophylaxis were compared with data from 22 historical controls. Absence of significant release of TNF alpha in the period of busulphan (BUS) treatment, but significant induction of TNF alpha by total body irradiation (TBI) and cyclophosphamide (CY) conditioning were correlated with significantly earlier onset of acute GVHD in patients receiving TBI/CY regimens as compared with BUS/CY-treated patients. Prophylactic application of monoclonal anti-TNF alpha seemed to postpone onset of acute GVHD from day 15 to day 25 (P < .05) after TBI/CY and from day 33 to day 53 after BUS/CY (P < .10) conditioning. Application of monoclonal anti-TNF alpha in low and intermediate doses was safe and not associated with an increased incidence of infectious or hematologic complications. Thus, our data provide indirect and direct evidence for involvement of conditioning-related cytokine release in induction of early acute GVHD in the clinical setting and support further investigation of this novel approach in randomized trials.