Bleeding Period Research Articles

Effects of three esca-associated fungi on Vitis vinifera L.: V. Changes in the chemical and biological profile of xylem sap from diseased cv. Sangiovese vines

A vineyard of Vitis vinifera cv. Sangiovese was surveyed for incidence of esca and xylem sap collection. Sap samples were collected from healthy vines and from those with dual infection by Phaeomoniella chlamydospora ( Pch) and Togninia minima ( Tmi) or triple infection by Pch, Tmi and Fomitiporia mediterranea ( Fme), during each early spring in a 3-year period (2001–2003). In order to analyse the possible trends in the climatic data, temperature and rainfall were assessed. At sap harvesting, aliquots of sap were assayed for phytotoxicity and extracted with ethyl acetate for phytotoxin recovery. Moreover, the exopolysaccharide (EPS) content was evaluated on several sap samples during the bleeding period. Conidia of Pch and Tmi, mycelium of Fme and their secondary metabolites were found in the sap of the esca-affected vines, indicating that the pathogens and their by-products together with some defence substances were accumulated and then translocated. Bioactivity tests showed toxicity of the sap from esca-affected vines to healthy detached leaves of cv. Sangiovese. The daily amount of sap, the pH, and the volume ( J v ) and solute ( J s ) fluxes were analysed as a function of the infecting fungi. Pullulan, glucogalactomannan(s) and arabinogalactan(s) are the main EPS in the esca-infected vines, whereas in the sap of healthy vines no traces of pullulan were found. Scytalone and isosclerone usually produced in vitro by Pch and Tmi were also detected in the sap of vines infected by Pch and Tmi or by Pch, Tmi and Fme. The endogenous phytohormone content of healthy vines evaluated by the cutting bioassay was different from that of infected vines. Four phenolics belonging to three classes e.g., benzoic acid derivatives, stilbenes and flavonol-glycosides were separated and identified by HPLC.

Predictors of oligoamenorrhea at 1-year follow-up in premenopausal women using a levonorgestrel-releasing intrauterine system

Objective The study was conducted to identify predictors of oligoamenorrhea at 12 months in levonorgestrel-releasing intrauterine system (LNG-IUS) users. Design A 12-month observational study. Setting Gynecologic outpatient clinic in a large regional hospital in Flanders, Belgium. Population or Sample A total of 150 women who had made an informed decision to use a LNG-IUS either as a method of contraception or to manage menorrhagia. Methods All women were premenopausal and first-time users. The variables recorded prior to insertion on Days 1 to 5 of the menstrual cycle were age, parity, body mass index, indication for LNG-IUS use, prior contraceptive use, menstrual bleeding history, length of the uterine cavity, endometrial thickness, number of antral follicles, serum follicle-stimulating hormone, inhibin B and anti-Müllerian hormone. Menstrual bleeding pattern, patient satisfaction or wish to discontinue the method was noted at 3, 6 and 12 months of follow-up visits. Main Outcome Measures Menstrual bleeding pattern (amenorrhea, oligomenorrhea, menorrhagia) at 12 months was taken as the primary outcome measurement. Patient satisfaction was followed as a secondary outcome. Results Oligoamenorrhea was associated with a high patient satisfaction. A bleeding period less than 5 days, absence of severe uterine bleeding at baseline, LNG-IUS use for contraception and oligoamenorrhea at 3 months were predictors of a favorable outcome at 12 months in a univariate analysis. The absence of severe bleeding prior to LNG-IUS insertion was the only clinically useful predictor of favorable outcome in the multivariate analysis (odds ratio 0.13, 95% confidence interval 0.02–0.66). Conclusions Patient profiling as described is not helpful in counselling women for intentional LNG-IUS use, especially not if it is planned as a method of managing menorrhagia.

Clinical profile of 24-day oral contraceptives

24-day oral contraceptives are low-dose oral contraceptives that extend the active pill cycle from the traditional 21 days to 24 days. A 24-day regimen is associated with less breakthrough bleeding and shorter withdrawal bleeding periods. Extending the number of days with active pill taking results in less ovarian activity, a consequence of greater gonadotropin suppression during the pill-free interval. A reduction in ovarian activity can reduce the possibility of breakthrough ovulations and contraceptive failure.

The Impact of Self-perceived Job Stress on Menstrual Patterns among Taiwanese Nurses

The purpose of this study was to assess the impact of self-reported job stress on menstrual patterns among nurses. We conducted a cross-sectional survey of nursing staff from five psychiatric institutions and four general hospitals in Taiwan. A total of 746 participants were eligible for the final analysis, among whom, 72.3% were ascertained as having a self-perceived high level of job stress. Self-perceived high job stress was significantly associated with irregular menstrual cycles [Adjusted odds ratio (AOR): 4.8, 95% confidence interval (CI): 3.3-7.2] and longer menstrual bleeding periods (more than 7 d) [AOR: 2.5, 95% CI: 1.7-3.7], but was not significantly related to long or short menstrual cycles. Overall, this study suggests that nurses' self-perceived job stress may be associated with certain aspects of menstrual dysfunction. Further investigations with prospective follow-up studies and urine hormonal measurements are now recommended to provide additional insight into the pathophysiological mechanisms of our findings.

Menstrual Cycle Characteristics and Reproductive Patterns in Women Exposed to Atrazine in Drinking Water

P-343 Introduction: Atrazine is the most commonly used herbicide in the United States. The biological properties of atrazine suggest human exposure could result in adverse reproductive outcomes and impaired fertility. Concern regarding the potential health effects of human exposure to atrazine is based on its designation as an endocrine disruptor. Menstrual cycle characteristics provide an indicator of reproductive health and endocrine function. Adverse menstrual cycle characteristics have been associated with disturbances of luteinizing hormone (LH). Since LH is essential for normal menstrual function, a reduction in the LH surge can affect the ovarian cycle and lead to an altered menstrual cycle. We conducted a study to determine whether women exposed to atrazine in municipal drinking water experienced menstrual cycle abnormalities when compared to women not exposed to atrazine and whether these abnormalities were modulated through a dimunition of the pre-ovulatory luteinizing hormone surge. Methods: This study was comprised of total of 103 women 18 to 40 years old residing in two agricultural communities, one with atrazine exposure and one without. To evaluate the association between atrazine exposure and menstrual cycle characteristics via LH suppression, menstrual cycle characteristics were assessed prospectively using menstrual cycle diaries and retrospectively using questionnaire data. Women kept diaries through two menstrual bleeding periods. Endocrine hormone levels were evaluated in 36 women by collecting daily urine samples through two menstrual periods. Luteinizing hormone peaks were analyzed using commercial noncompetitive, two-site, time-resolved immunofluorometric assays. The major of urinary metabolites of estradiol and progesterone were assessed using competitive, double-antibody time-resolved fluoroimmunoassays. Exposure was assessed via municipal water system monitoring as well as through tap water samples collected at the participant’s residence and analyzed for atrazine and its twelve degradates. Results: Preliminary results will be presented and discussed at the conference. Discussion: This is the first study to prospectively examine the effects of atrazine on menstrual function. To our knowledge, it is also the first to examine the potential underlying mechanism of this association. Although several European countries have banned atrazine, approximately 32 million kilograms are applied annually to crops in the US where it has been identified in approximately 70% of agricultural and urban rivers. Despite atrazine’s ubiquitousness, little is known about its adverse health effects, particularly reproductive effects, in humans.

Toxic effects of methoxychlor on the episodic prolactin secretory pattern: possible mediated effects of nitric oxide production.

BackgroundThis work addresses the issue of whether methoxychlor (MTX) exposure may modify the ultradian secretion of prolactin through changes in the synthesis of nitric oxide (NO) induced by Nω-nitro-L-arginine methyl ester (L-NAME) in the hypothalamic-pituitary axis. Associated changes in dopamine (DA) content in the anterior (AH), mediobasal (MBH) and posterior hypothalamus (PH) and median eminence (ME) were evaluated.MethodsTwo groups of animals (MTX and MTX+L-NAME treated) received subcutaneous (sc) injections of MTX at a dose of 25 mg/kg/day for one month. The other two groups of animals (control and L-NAME treated) received sc vehicle injections (0.5 mL/day of sesame oil), during the same period of time to be used as controls. Forty hours before the day of the experiment, animals were anaesthetized with intrapritoneal injections of 2.5% tribromoethanol in saline and atrial cannulas were implanted through the external jugular vein. Plasma was continuously extracted in Hamilton syringes coupled to a peristaltic bomb in tubes containing phosphate-gelatine buffer (to increase viscosity). The plasma was obtained by decantation and kept every 7 minutes for the measurement of plasma prolactin levels through a specific radioimmnunoassay and DA concentration by high-pressure liquid chromatography (HPLC).ResultsProlactin release in animals from all experimental groups analyzed was episodic. Mean plasma prolactin levels during the bleeding period, and the absolute pulse amplitude were increased after MTX or Nω-nitro-L-arginine methyl ester (L-NAME) administration. However MTX and L-NAME did not modify any other parameter studied with the exception of relative pulse amplitude in MTX treated rats. L-NAME administration to rats treated with the pesticide reduced mean plasma prolactin levels and the absolute amplitude of prolactin peaks. Peak duration, frequency and relative amplitude of prolactin peaks were not changed in the group of rats treated with MTX plus L-NAME as compared to either control or MTX treated rats. Whereas MTX decreased DA content in the ME and increased it in the AH, its content did not change in the MBH or PH, as compared to the values found in controls. Also, L-NAME administration decreased DA content in the ME as compared to controls. However, L- NAME administration to MTX exposed rats, markedly increased DA content in the ME as compared to either MTX treated or control rats. L-NAME administration increased DA content in the AH as compared to the values found in non-treated rats. However L-NAME administration to MTX exposed rats did not modify DA content as compared to either MTX treated or control rats. L-NAME administration did not modify DA content at the MBH nor in saline treated nor in MTX treated rats. However, the values of DA in the MBH in MTX plus L-NAME treated animals were statistically decreased as compared to L-NAME treated rats. In the PH, L-NAME administration increased DA content as compared to the values found in non-treated animals. L-NAME administration to MTX exposed rats also increased DA content as compared to either MTX treated or control rats.ConclusionThe results suggest the existence of an interaction between MTX and L-NAME in the modulation of the ultradian prolactin secretion at the pituitary levels. The possibility of an indirect effect mediated by changes in DA content at the ME requires further examination.

Sequential patterns of haemodynamic and metabolic changes in experimental hypovolaemic shock. I. Responses to acute haemorrhage.

Little is known about cardiorespiratory changes during the development of hypovolaemia. This study attempts to provide such information and compares the period of bleeding with that of established hypovolaemia. Eleven anaesthetized and ventilated greyhounds were bled and analyses of cardiopulmonary function made at fixed intervals both during and after haemorrhage. Six sequential patterns of cardiopulmonary and metabolic change were recognized. It was apparent that bleeding caused the first three phases of change, recovery from the effects of bleeding the next two and steady hypovolaemia the last. The event of bleeding is the main factor that elevates total peripheral resistance and reduces tissue perfusion with consequent lowering of oxygen consumption and alkalosis secondary to impaired carbon dioxide production; when bleeding ceases these changes partially reverse in a manner characteristic of that induced by the reinfusion of shed blood; and hypovolaemia per se has a relatively weak influence. These findings provide an explanation for disparities in previous published reports and have obvious clinical implications.

Menstrual function during methadone maintenance (MM)

Background While heroin use is known to disrupt menstruation, little has been published on menstruation and MM. We evaluated whether cycles were more regular during MM. Methods Participants were 154 polydrug-using women in MM (70–100 mg/d), not on hormonal therapy, pregnant, or postmenopausal. Cycle length and bleeding days were calculated from start and end dates of each bleeding period (data collected weekly for up to 39 weeks). Women were classified as having regular or irregular cycles, transient or persistent amenorrhea, or cycle restart. Correlates of cycle length and the probability of a long or short cycle were determined by repeated-measures regression. Relationships among cycle length, body mass index, drug use, methadone dose, and race were analyzed. Results Cycle-length irregularity was common: Regular 27.8%; irregular 46.7%; transient amenorrhea 5.3%; persistent amenorrhea 8.3%. Improvement occurred with MM: each additional week on MM was associated with decreased risk of both long (>40 d; OR=0.96, p=0.001) and short (>20 d; OR=0.92, p=0.001) cycles, and 16 of 27 women amenorrheic at study entry restarted menses. Conclusions Benefits of MM may include normalization of menstrual cycle and resolution of secondary amenorrhea due to heroin use and associated morbidity. Clinical Pharmacology & Therapeutics (2005) 77, P65–P65; doi: 10.1016/j.clpt.2004.12.140

Effect of Finishing Practices on Performance of Concrete Containing Slag and Fly Ash as Measured by ASTM C 672 Resistance to Deicer Scaling Tests

Abstract The test method was developed to evaluate portland cement systems with different air contents, and for the purpose of determining whether the apparent poor performance of concretes containing supplementary cementing materials in the ASTM C 672 deicer scaling test can be attributed to differences in finishing effort or timing of finishing, or both.

Experience of Menarche among Girls in Alexandria: Community-Based Study, Alexandria 2003

Background: The age at menarche is an important factor in health planning and is known to be influenced by genetic factors, environmental conditions, body stature, and socio-economic status. Aim of the work: The present study was carried out to determine the average age at menarche and pattern of menstruation among girls of Alexandria, also to identify predictions of age at menarche and to assess knowledge and practice of girls in Alexandria about menarche and menstrual hygiene. Subjects and Methods: A descriptive, cross-sectional epidemiological approach was chosen. A total of 900 recently menstruating girls and their mothers were randomly selected using a cluster random sampling method. The data were collected using a questionnaire. Body mass index [BMI] was used as indicator of nutrition. Data about girls’ knowledge and practices related to menstruation were assessed. The traditional practices of mothers concerning their daughters’ menarche were identified. Principal Component Factor Analysis [PCFA] was applied to reduce numerous interrelated socio-economic variables under study to independent components in order to allow better interpretations. A stepwise multiple regression analysis was performed to determine the joint contribution of the significant variables to age at menarche of the studied girls. Results: Age at first menstruation of the studied girls ranged between 10 to 14.5 years with a mean age of 11.91+0.93 years. Late menarche is significantly correlated to irregular menstruation, prolongation of both menstrual cycle and bleeding period, and more symptoms associated with menstruation. Age of mothers’ menarche [b=0.101], body mass index [b=-0.165], socio-economic index [b=-0.137], winter [b=0.107], spring [b=-0.127], summer [b=-0.107] and autumn [b=0.127] were identified as significant predictors of age at menarche in the studied girls. Findings revealed that 59.1% of girls had not any information about menstruation before menarche and had significantly higher negative feelings than those who were prepared [x4=109.43, P<0.001]. The mean percent score of knowledge among all the studied girls, regarding menarche and menstrual hygiene, was 39.86+21.85% while that for their health take caring practices was 41.25+14.44%. The mean percent score of health take caring practices for girls who were prepared before menarche [44.26+13.19%] was significantly higher than that for unprepared ones [36.67+13.41%] where t=4.864 [P<0.001]. However, insignificant correlation was observed between percent score of girls’ knowledge and that of their health take caring practices [r=0.091, P=0.113]. The mean percent score of mothers’ healthful practices related to their daughters’ menarche was 66.71+17.44%. Conclusion: The study revealed lack of appropriate and sufficient information regarding menstruation and its hygiene among Alexandria girls. Consequently, they adopt some unhealthy practices during menstruation which were found to have a socio-cultural origin. Issue of puberty should be emphasised in school health program during early school years. In addition, a community-based health education program focusing on menstruation and its hygiene should be launched for mothers. Further similar studies are recommended in other regions of Egypt for identification of sub-cultural similarities and variations to provide a comprehensive picture for Egypt.

Influence of Patient Selection on the Outcome of Capsule Endoscopy in Patients with Chronic Gastrointestinal Bleeding

BACKGROUND The published success rates of capsule endoscopy (CE) in the detection of definite bleeding sources in patients with chronic gastrointestinal bleeding (CGB) range from 48 to 76%. Up to now, the influence of selection of the patients on the number of positive findings in the CE, is not clear. METHODS Between April 2001 and Juni 2003 127 patients with CGB and suspected bleeding source in the small bowel were referred to our unit. In 74 patients (58%) CE was performed; 70 of these 74 patients could be enrolled in the analysis. These 70 patients (32 men, 38 women) with a mean age of 57.8 (range 14 to 90) years were devided into two groups: the so-called study group (32 patients; prospective study, published in Endoscopy 2002) and the post-study group (38 patients, retrospective analysis). The patients data and results of CE of these two groups were compared with one another. RESULTS In the study group the selection of patients was done with more restraint than in the post-study group: 49% (32/65) vs. 65% (38/58) patients received a CE. The overall success rate of CE in the detection of definite bleeding sources was 54% (38/70 pats.); in the study group in 66% (21/32 pats.) and in the post-study group only in 45% (17/38 pats.) a relevant bleeding source could be seen. There were no significant differences regarding the patients data such as age, sex, taking of anticoagulant medication, duration of CGB and type of bleeding (overte, occult). Significant differences were found as follows: in the study group the lowest hemoglobin level (mean 5.9g/dl) was significant lower than in the post-study group (mean 7,7 g/dl) and the number of blood units that had been transfused was significant higher in the study group (median of 10 units vs. 2 units in the post-study group). No patient with a lowest hemoglobin level during the bleeding period of more than 10g/dl had a positive CE. CONCLUSION The selection of patients is very important for the success rate of CE. In case of patients with CGB the lowest hemoglobin level and the number of blood transfusions seem to be the main factors.

Abnormal uterine bleeding and prognosis of endometrial cancer

Objectives: The aim of this study was to analyze the relationship between the period of abnormal uterine bleeding (AUB) and the prognosis of endometrial cancer. Methods: We reviewed 304 endometrial cancer patients who were diagnosed and treated between 1985 and 1998 in our hospital, and whose history of AUB and clinical parameters were clearly available from their charts. Pathological data and overall survival were compared between groups having different periods of AUB. Results: Duration of AUB had no impact on the prognosis of endometrial cancer. Patients diagnosed with endometrial cancer without AUB showed a significantly better 5-year overall survival rate than the patients diagnosed after the onset of AUB. The distribution of clinical stages and histological grades did not differ depending on AUB status. Conclusions: The prognosis of endometrial cancer was determined by the histopathological character of the tumor. However, the diagnosis and treatment of endometrial cancer with some suspicious signs other than AUB might improve the prognosis.

Simulation of the Cardiovascular System Using PID Control Model

Objective The electric analog circuit model can be used to analyse the various function of the cardio vascular system and the dynamic characteristics on each part of human body. According to the previous studies, viscous resistance, flow inertia, and vascular compliance in the cardiovascular system are analogous to resistance, inductance, and capacitance in electric circuit, so the cardiovascular system models have been represented by the electric circuit models. These approaches were to propose suitable models for the interested part of body and to simulate the various characteristics on the cardiovascular system. Methods This paper tried to put the characteristics of morphologic structure into the suggested electric circuit model. After setting parameter values of the model the dynamic characteristics of the cardio vascular system is simulated using VisSim, which is one of the simulation tools. Results The derived simulation results have represented major cardiovascular functions of normal adults. Also simulation results reflect the variation due to the pathophysiological state. Conclusion The controller by baroreceptor, which is one of controllers to control the cardiovascular system, is appended in the model. The dynamic response characteristics and the procedure to restore blood pressure to normal state was observed by simulation lasted a certain period of bleeding.

Effect of nitric oxide on prolactin secretion and hypothalamic biogenic amine contents

Involvement of nitric oxide (NO) in the episodic secretion of prolactin was studied in conscious freely moving adult rats. Prolactin secretion was pulsatile in all animals of either group during the bleeding period (from 10:30 h to 13:30 h). Administration of N ω-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, increased mean plasma levels of prolactin, and the absolute amplitude of prolactin peaks during the whole bleeding period as compared to values found in the control group. L-NAME increased norepinephrine (170%), dopamine (58.27%) and serotonin contents (30%) in the anterior hypothalamus. In the median eminence, dopamine and serotonin contents decreased (19.79% and 33.9% respectively) after L-NAME as compared to the values found in controls. In addition, norepinephrine content increased in mediobasal hypothalamus (79.6%) of rats treated with L-NAME. The results indicate that changes in NO production may modify the episodic secretion of prolactin. These effects were associated with changes in hypothalamic and median eminence biogenic amines.

Conservative treatment by angiographic artery embolization of an 11-week cervical pregnancy after a period of heavy bleeding

Objective To describe a rare case of conservative treatment of an 11-week cervical pregnancy after a period of heavy bleeding. Design Case report. Setting A university hospital. Patient(s) A 33-year-old woman was admitted to our hospital for treatment of a cervical pregnancy. Two-and-a-half years thereafter, she gave birth to a healthy baby by vaginal delivery at 38 weeks of gestation. Intervention(s) Systemic methotrexate treatment, ligation of descending branches of uterine arteries, cervical cerclage, and unilateral internal iliac artery embolization. Main outcome measure(s) Transvaginal ultrasound, magnetic resonance imaging, and arteriography findings. Result(s) The patient was successfully treated with unilateral internal iliac artery embolization on the same side as the pregnancy in the 11th gestational week. Conclusion(s) After failed methotrexate and vessel ligation in cervical pregnancy, unilateral internal iliac artery embolization is an effective and conservative treatment that allows preservation of reproduction potential.

Continuous intrauterine compared with cyclic oral progestin administration in perimenopausal HRT

Objectives: Two hormone replacement therapy (HRT) regimens of combined oral estradiol with either continuous intrauterine or cyclic oral progestin were compared for 2 years. Methods: 200 perimenopausal women randomly received an intrauterine system with continuous levonorgestrel release (20 μg/24 h) combined with oral estradiol (2 mg daily), or a cyclic oral regimen of norethisteroneacetate (1 mg on day 13–22) and estradiol (days 1–21; 2 mg, days 22–28; 1 mg). Efficacy on endometrial protection, vaginal bleeding patterns, blood loss and practical use were compared during 26 cycles. Results: Endometrial protection was adequate in both regimens. The cyclic regimen induced a more regular bleeding pattern. The continuous local administration induced a reduction in bleeding ( P=0.001) with an initial period of prolonged and frequent bleeding. 38% became ameorrhoeic. Women found both regimens acceptable. Conclusions: Continuous intrauterine Levonorgestrel administration by using an intrauterine system can well be recommended for use in combination with oestrogen replacement therapy in perimenopausal women.

Evidence for a role of nuclear factor-κB in acute hypovolemic hemorrhagic shock

Background. In acute hypovolemic shock, a rapid systemic release of the inflammatory cytokine tumor necrosis factor (TNF-α) contributes to vascular failure. Nuclear factor κB (NF-κB) is an ubiquitous rapid-response transcription factor involved in inflammatory reactions and exerts its effect by expressing cytokines, chemokines, and cell adhesion molecules. The purpose of this study was to evaluate the role of NF-κB in acute hypovolemic hemorrhagic shock. Methods. Hemorrhagic shock was induced in anesthetized male rats by intermittently withdrawing blood from an iliac catheter for 20 minutes (bleeding period) until mean arterial blood pressure (MAP) decreased and stabilized within the range of 20 to 30 mm Hg. Two minutes after bleeding was discontinued the rats received tacrolimus (100 μg/kg), an inhibitor of NF-κB activation, or its vehicle. We then evaluated survival rate and survival time, liver NF-κB activation by means of electrophoretic mobility shift assay, liver IκBα protein in the cytoplasm, hepatic TNF-α messenger RNA expression, plasma TNF-α, arterial blood pressure, and the contractile response of aortic rings to phenylephrine. Results. Rats that underwent hemorrhagic shock died 28 ± 2 minutes after bleeding was discontinued, experienced marked hypotension (MAP, 20-30 mm Hg), and had enhanced plasma levels of TNF-α (218 ± 28 pg/mL 20 minutes after bleeding was discontinued). Aortas taken 20 minutes after bleeding was discontinued in rats that underwent hemorrhagic shock showed marked hyporeactivity to phenylephrine (1 nmol/L-10 μmol/L) compared with aortas harvested from sham shocked rats. Rats that underwent hemorrhagic shock also had increased levels of TNF-α messenger RNA in the liver. Furthermore, electrophoretic mobility shift assay showed that liver NF-κB binding activity increased in the nucleus, and Western blot analysis suggested that the levels of inhibitory IκBα protein in the cytoplasm decreased. Tacrolimus (100 μg/kg, administered 2 minutes after bleeding was discontinued) inhibited the loss of IκBα protein from the cytoplasm and prevented NF-κB binding activity in the nucleus. Moreover, tacrolimus increased survival time (118 ± 7 minutes; P <.01) and survival rate (vehicle = 0 and tacrolimus = 90% 240 minutes after bleeding was discontinued), reverted the marked hypotension, decreased liver messenger RNA for TNF-α reduced plasma TNF-α (35 ± 6 pg/mL), and restored the hyporeactivity to phenylephrine to control values. Conclusions. Our results suggest that acute blood loss (50% of the estimated total blood volume during a 20-minute period) causes activation of NF-κB and that tacrolimus, by inhibiting this transcription factor, protects against acute hypovolemic shock. (Surgery 2002;131:50-8.)

Nuclear factor-kappaB as a target of cyclosporin in acute hypovolemic hemorrhagic shock.

Cyclosporin is an immunosuppressive drug that blocks Nuclear Factor kappaB (NF-kappaB) activation. We investigated the role of NF-kappaB in acute hypovolemic hemorrhagic (Hem) shock and the effects of cyclosporin in this model of experimental shock. Hem shock was induced in male anesthetized rats by intermittently withdrawing blood from an iliac catheter over a period of 20 min (bleeding period) until mean arterial blood pressure (MAP) fell and stabilized within the range of 20-30 mmHg. Two minutes after bleeding cessation, animals received intravenously cyclosporin (1 mg kg(-1)) or its vehicle. Survival rate and survival time were evaluated for 120 min after bleeding was discontinued. Plasma TNF-alpha levels were investigated at different time points after bleeding cessation. Moreover we investigated levels of TNF-alpha mRNA in the liver, vascular reactivity, liver NF-kappaB binding activity and levels of the inhibitory protein IkappaBalpha in the cytoplasm. Hemorrhagic shocked rats died in 27+/-6 min following the cessation of bleeding, experienced a marked hypotension (mean arterial blood pressure=20-30 mmHg) and had enhanced plasma levels of Tumor Necrosis Factor-alpha (208+/-22 pg ml(-1), 20 min after the end of bleeding). Furthermore, aortas taken 20 min after bleeding from hemorrhagic shocked rats showed a marked hypo-reactivity to phenylephrine (PE: 1 nM-10 microM) compared with aortas harvested from sham shocked rats. Hem shocked rats also had increased levels of TNF-alpha mRNA in the liver (15-20 min after the end of bleeding). Electrophoretic mobility shift assay showed that liver NF-kappaB binding activity increased in the nucleus 10 min after the end of hemorrhage and remained elevated until the death of animals. Western blot analysis suggested that the levels of inhibitory protein IkappaBalpha in the cytoplasm decreased at 5 min after the end of bleeding. Cyclosporin inhibited the loss of IkappaBalpha protein from the cytoplasm and prevented NF-kappaB binding activity in the nucleus. Furthermore, cyclosporin increased survival time (118+/-7 min; P<0.01) and survival rate (vehicle=0% and cyclosporin=80%, at 120 min after the end of bleeding), reverted the marked hypotension, decreased liver mRNA for TNF-alpha, reduced plasma TNF-alpha (28+/-7 pg ml(-1)), and restored to control values the hypo-reactivity to PE. Our results suggest that acute blood loss (50% of the estimated total blood volume over a period of 20 min) causes early activation of NF-kappaB which triggers an inflammatory cascade leading to a fatal outcome. Cyclosporin blocks NF-kappaB activation and protects against hypovolemic hemorrhagic shock.

Open, multicenter comparison of efficacy, cycle control, and tolerability of a 23-day oral contraceptive regimen with 20 μg ethinyl estradiol and 75 μg gestodene and a 21-day regimen with 20 μg ethinyl estradiol and 150 μg desogestrel

This prospective, open, randomized study was conducted to compare the contraceptive reliability, cycle control, and tolerability of a 23-day regimen with 20 μg ethinyl estradiol (EE) and 75 μg gestodene (GSD) and a 21-day regimen with 20 μg EE and 150 μg desogestrel (DSG). Participants took either 23 tablets with active substances plus 5 placebo tablets (23-day EE/GSD) or 21 tablets with active substances followed by 7 days without pill-taking (21-day EE/DSG). Contraceptive efficacy, cycle control, and tolerability were evaluated over a period of seven cycles. Efficacy data gathered from 5967 treatment cycles (23-day EE/GSD: 2975 cycles; 21-day EE/DSG: 2992 cycles) were obtained from 890 participants (445 in each group). Both preparations proved to be effective contraceptives and provided good cycle control. No pregnancy during treatment was recorded. This resulted in a study Pearl Index of 0.0 for both treatments. For 23-day EE/GSD, 32.4% of participants reported at least one intracyclic bleeding episode during Cycles 2–4 (primary target) compared to 31.5% for 21-day EE/DSG. In the 23-day EE/GSD group, intracyclic bleeding episodes were reported by 48.8% of the participants in Cycle 1 but in only 15.1% in Cycle 7, and in the 21-day regimen group by 43.4% in Cycle 1 and only 14.2% in Cycle 7. Overall, intracyclic bleeding was reported in 20.9% of cycles for both treatments. A greater number of 23-day EE/GSD participants had shorter withdrawal bleeding periods than with 21-day EE/DSG. In significantly (p <0.0001) more cycles in the 23-day EE/GSD group participants reported withdrawal bleeding periods that lasted only 1–4 days compared to the 21-day EE/DSG group. For the majority of the treatment cycles, the median number of bleeding days in the 23-day EE/GSD group was 4 days and in the 21-day EE/DSG group 5 days. Both preparations were well tolerated and showed a similar adverse events pattern. The discontinuation rate because of adverse events was low (23-day EE/GSD: 6.1%; 21-day EE/DSG: 5.6%). No serious vascular adverse events were reported. More than 82% in the 23-day EE/GSD group and 79% in the 21-day EE/DSG group either lost more than 2 kg of weight or did not gain weight during the study. The treatment effect on blood pressure was negligible. There were no appreciable changes in mean laboratory values over the course of the study compared to baseline.

Double-blind, multicenter comparison of efficacy, cycle control, and tolerability of a 23-day versus a 21-day low-dose oral contraceptive regimen containing 20 μg ethinyl estradiol and 75 μg gestodene

This prospective, double-blind, randomized study was conducted to compare the contraceptive reliability, cycle control, and tolerability of a 23-day versus a 21-day oral contraceptive regimen containing 20 μg ethinyl estradiol and 75 μg gestodene. Participants took trial medication daily for 28 days, either 23 tablets with active substances plus 5 placebo tablets or 21 tablets with active substances plus 7 placebo tablets. Contraceptive efficacy, cycle control, and tolerability were evaluated over a period of seven cycles. Efficacy data gathered from 4,878 treatment cycles (23-day regimen: 2,362 cycles; 21-day regimen: 2,516 cycles) were obtained from 703 participants (23-day regimen, n = 342; 21-day regimen, n = 361). Both preparations proved to be effective contraceptives and provided good cycle control. One pregnancy because of method failure was recorded in each treatment group. This resulted in a study Pearl Index of 0.5 for each treatment. For the 23-day regimen, 36.0% of participants reported at least one intracyclic bleeding episode during Cycles 2–4 (primary target) compared to 37.1% in the 21-day regimen. In the 23-day regimen group, intracyclic bleeding episodes were reported by 42.4% of the participants in Cycle 1 but only in 14% in Cycle 7 and in the 21-day regimen group by 44.6% in Cycle 1 and only 17.3% in Cycle 7. Overall, intracyclic bleeding was reported in 21.9% of the 23-day regimen cycles and in 22.7% of the 21-day regimen cycles. A greater number of 23-day regimen participants had shorter withdrawal bleeding periods than with the 21-day regimen. In significantly (p <0.0001) more cycles in the 23-day regimen group, participants reported withdrawal bleeding periods that lasted only 1–4 days compared to the 21-day regimen group. For the majority of the treatment cycles, the median number of bleeding days in the 23-day regimen group was 4 days and in the 21-day regimen group 5 days. Both preparations were well tolerated and showed a similar adverse events pattern. The discontinuation rate because of adverse events was low (23-day regimen, 6%; 21-day regimen, 4%). No serious vascular adverse events were reported. More than 75% of the women in both groups either lost more than 2 kg of weight or did not gain weight during the study. The treatment effect on blood pressure was negligible. There were no appreciable changes in mean laboratory values over the course of the study.