Acute aortic occlusion after microendoscopic laminectomy in a patient with lumbar spinal stenosis: A case report.

RATIONALE: Acute aortic occlusion is an uncommon disease with a high morbidity and high mortality. Clinical symptoms typically include acute lower limb pain, acute paralysis, and absent pulses. We report a very rare case of acute aortic occlusion causing complete paralysis of bilateral lower limbs following microendoscopic laminectomy. PATIENT CONCERNS: A 64-year-old man with hypertension, hyperlipidemia, diabetes, and atrial fibrillation underwent microendoscopic laminectomy for lumbar spinal stenosis. After the operation, intermittent claudication improved significantly without neurological deficit. However, 7 days later, he developed complete paralysis of the bilateral lower limbs, extreme pain of the bilateral lower limbs, and mottling of the left extremity. DIAGNOSIS: An emergency magnetic resonance imaging examination revealed no epidural hematoma behind the spinal cord, proscribing spinal cord compression. Computed tomography revealed occlusion of the infrarenal abdominal aorta. Blood tests revealed high values of total plasminogen activator inhibitor-1 before surgery. INTERVENTIONS: The acute aortic occlusion was verified and underwent thrombectomy and right axillary-bifemoral bypass. OUTCOMES: Following the revascularization, the neurological deficit of the lower limbs improved. On follow-up after 1 year, the muscle strength of the bilateral lower limbs had returned to normal. LESSONS: This case presentation highlights the necessity of early diagnosis and early revascularization. Moreover, a preoperative high value of plasminogen activator inhibitor-1 may indicate vascular complications including Acute Aortic Occlusion.

A prospective study of soluble receptor for advanced glycation end products and adipokines in association with pancreatic cancer in postmenopausal women.

Advanced glycation end products (AGEs) dysregulate adipokines and induce inflammation by binding to their adipocyte receptor (RAGE). Soluble RAGE (sRAGE) prevents AGEs/RAGE signaling. We performed a nested case-control study of the association between sRAGE, adipokines, and incident pancreatic cancer risk in the prospective Women's Health Initiative Study. We individually matched controls (n = 802) to cases (n = 472) on age, race, and blood draw date. We evaluated serum concentrations of sRAGE, adiponectin, leptin, monocyte chemotactic protein 1 (MCP1), and plasminogen activator inhibitor-1 (PAI1) using immunoassay. We used conditional logistic regression model to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for pancreatic cancer over biomarker quartiles (Q1-Q4). We used principal component analysis to create two composite biomarkers and performed a confirmatory factor analysis to examine the association between composite biomarker scores (CBS) and pancreatic cancer risk. Baseline serum sRAGE concentrations were inversely associated with pancreatic cancer risk (aORQ4 vs. Q1  = 0.70, 95% CI: 0.50-0.99). High MCP1 (aOR Q4 vs. Q1  = 2.55, 95% CI: 1.41-4.61) and the higher CBS including MCP1, PAI1, and leptin (aORQ4 vs. Q1  = 1.82, 95% CI = 1.04-3.18) were also associated with increased pancreatic cancer risk among women with BMI <25 kg/m2 (P values for interaction <0.05). We found an inverse association between prediagnostic sRAGE concentrations and risk of incident pancreatic cancer in postmenopausal women. A proinflammatory CBS was associated with increased risk only in women with normal BMI. MCP1 was not modulated by sRAGE.

Subtle to severe hepatobiliary morbidity in Opisthorchis viverrini endemic settings in southern Laos.

Evidence of severe hepatobiliary morbidity associated with Opisthorchis viverrini liver fluke infection including cholangiocarcinoma (CCA) is scarce in Laos although O. viverrini infection is highly prevalent. We assessed hepatobiliary morbidity using abdominal ultrasonography (US) in O. viverrini adult patients in Saravan province, Southern Laos. A random sample of 431 O. viverrini patients from 10 villages underwent abdominal US. Mild, moderate and markedly advanced periductal fibrosis was diagnosed in 7.0%, 66.5%, and 17.0% of patients, respectively. Normal liver parenchyma was seen in only 9.5% of patients. Presence of gall stones (13.2%), sludge (1.4%), gall wall thickening (1.2%), bile duct dilatation (1.6%), fatty liver (12.0%), kidney stones (8.6%) and cysts (7.9%) were diagnosed in considerable frequencies. In five patients (1.2%) hepatobiliary lesions suggesting CCA were diagnosed. Tumour markers, i.e. Interleukin-6, plasminogen activator inhibitor and carbohydrate antigen 19-9 were within normal range. The number of CCA suspected liver masses and hepatobiliary morbidity diagnosed among clinically asymptomatic adult patients in O. viverrini endemic area presents a major public health concern in Laos. However, definitive diagnosis of Opisthorchis-related severe sequelae including CCA is urgently needed to gauge the burden of this deadly disease in Laos.

[The correlation study of the expression of VEGF with t-PA and PAI expression in plasma and intraocular tissue in proliferative diabetic retinopathy].

OBJECTIVE: To evaluate the correlation between the expression of VEGF with t-PA and PAI expression in plasma aqueous humor and vitreous of proliferative diabetic retinopathy (PDR). METHODS: It was an experimental study. The concentrations of VEGF t-PA and PAI in plasma, aqueous humor and vitreous body in PDR and normal group were detected by ELISA. RESULTS: The levels of VEGF (53.37 ng/L) and PAI (8.00 µg/L) in the plasma of PDR patients were higher than control group, and there was significant statistically difference between them (Z = -3.437, -5.816; P < 0.01). The levels of t-PA (24.32 µg/L) in plasma of PDR patients and control group was no statistically difference between them (Z = -1.715, P = 0.086). The levels of VEGF (335.00 ng/L) t-PA (5.70 µg/L) and PAI (0.63 µg/L) in the aqueous humor of PDR patients were higher than control group, and there was statistically difference between them (Z = -4.805, -1.967, -4.018; P < 0.05). The levels of VEGF (691.69 ng/L) t-PA (13.05 µg/L) and PAI (4.01 µg/L) in the vitreous of PDR patients were higher than control group , and there was statistically difference between them (Z = -2.807, -2.642, -2.230;P < 0.05). Compare the plasma aqueous humor and vitreous of PDR patients. The levels of VEGF is: vitreous>aqueous humor>plasma. The levels of t-PA is: plasma>vitreous>aqueous humor. The levels of PAI is: plasma and vitreous>aqueous humor. The expression of VEGF was highly correlated with t-PA and PAI in plasma aqueous humor and vitreous of PDR (P < 0.05). CONCLUSIONS: VEGF PAI in plasma, VEGF t-PA PAI in aqueous humor and vitreous were increases. The expression of VEGF was positive correlated with t-PA and PAI in plasma aqueous humor and vitreous of PDR.

Circulating apelin levels are associated with cardiometabolic risk factors in women with previous gestational diabetes.

PURPOSE: Women with previous gestational diabetes mellitus (pGDM) are at high risk for type 2 diabetes and cardiovascular disorders. In this study, we aimed to compare plasma apelin levels between women with and without pGDM, and to investigate the possible association of apelin with cardiometabolic risk factors. METHODS: Among 252 consecutive Caucasian women with GDM being included in a prospective postpartum follow-up protocol, 141 women eligible for the study protocol were enrolled. Control group consisted of 49 age- and body mass index-matched healthy women without pGDM. Circulating apelin, IL-6 and plasminogen activator inhibitor levels, and carotid intima media thickness (IMT) were measured. To evaluate carbohydrate intolerance, 75-g oral glucose tolerance test was performed. Fasting insulin and lipids were measured, and homeostasis model assessment index was calculated. RESULTS: Plasma apelin levels were reduced in women with pGDM (p < 0.001). In multiple regression analysis, apelin was negatively associated with fasting (r (2) 0.090, ß -0.273, p = 0.001) and post-load glucose (r (2) 0.061, ß -0.187, p = 0.022), serum IL-6 (r (2) 0.082, ß -0.234, p = 0.002), and carotid IMT (r (2) 0.057, ß -0.168, p = 0.033). CONCLUSIONS: Our results suggested that suppressed apelin levels were associated with increased cardiovascular risk in women with pGDM.

Effect of endovascular and open abdominal aortic aneurysm repair on thrombin generation and fibrinolysis.

BACKGROUND: Abdominal aortic aneurysm (AAA) is associated with a prothrombotic diathesis that may increase the risk of cardiovascular events. This diathesis is exacerbated in the short term by open aneurysm repair (OAR) and endovascular aneurysm repair (EVAR). However, the effect of EVAR and OAR on coagulation and fibrinolysis in the medium and long term is poorly understood. The purpose of this study was to investigate the medium-term effects of EVAR and OAR on thrombin generation, neutralization, and fibrinolysis. METHODS: Prothrombin fragment (PF)1+2, thrombin antithrombin (TAT) complex, plasminogen activator inhibitor (PAI) activity, and tissue-plasminogen activator (t-PA) antigen were measured in eight age-matched controls (AMCs), 29 patients with AAA immediately before (preoperatively) and 12 months after EVAR (post-EVAR), and in 11 patients at a mean of 16 months after OAR (post-OAR). RESULTS: Preoperatively, PF1+2 levels were significantly higher in patients with AAAs than in AMC. PF1+2 levels post-EVAR and post-OAR were significantly lower than preoperative values and similar to AMC. There was no significant difference in TAT, PAI, or t-PA between AMC, AAA preoperatively, and post-EVAR. Post-OAR, PAI activity was significantly higher than in preoperative patients. CONCLUSIONS: AAA is associated with increased thrombin generation without upregulation of fibrinolysis. The prothrombotic, hypofibrinolytic diathesis observed in patients with AAA returns toward normal in the medium term after EVAR and OAR, although there is a trend toward decreased fibrinolysis post-OAR.

Very high concentration of D-dimers in portal blood in patients with pancreatic cancer.

UNLABELLED: Nowadays, increasing attention has been focused on relation between increased D-dimer levels and cancer among patients without detectable thrombosis. The aim of the study was to measure plasma D-dimer levels in portal and peripheral blood in pancreatic cancer patients with absence of venous thromboembolism. MATERIAL AND METHODS: Fifteen consecutive patients hospitalized in the Department of General and Transplant Surgery of Medical University in Lódz, from January to March 2012 who underwent surgery due to a pancreatic cancer were enrolled. At laparotomy, portal and peripheral blood were sampled concurrently. D-dimer and fibrinogen levels were measured. Moreover, to investigate overall coagulation function prothrombin time (PT), prothrombin index (PI), international normalized ratio (INR), thrombin time (TT), activated partial thromboplastin time (APTT), TT and APTT index were evaluated. RESULTS: Peripheral plasma D-dimmer levels above normal range were found in 10/15 patients (66,67%), whereas D-dimer above normal values were confirmed in all portal blood samples. Mean D-dimer values were higher in portal than in peripheral blood (3279.37 vs 824.64, by 297%, p=0,025). These discrepancies were accompanied by normal limits of portal and peripheral levels of fibrinogen and comparable coagulation function indexes. CONCLUSION: Our preliminary study showed the close relation between activation of hemostasis, reflected by elevated D-dimers in portal blood and presence of pancreatic cancer. These data suggest that measurement of portal blood D-dimer levels may be a potentially useful technique for screening the pancreatic cancer.

Gene polymorphisms related to angiogenesis, inflammation and thrombosis that influence risk for oral cancer.

Genetic association studies have implicated functional DNA polymorphisms in genes encoding factors related to angiogenesis, inflammation and thrombosis with increased risk for oral squamous cell carcinoma (OSCC). This study examines possible interactions between nine such genotype polymorphisms and their combinatory effect in assessing the OSCC risk in a European population. OSCC cases (N=162) and healthy controls (N=168) of comparable age, gender, and ethnicity (Greeks and Germans) were studied. Multivariate logistic regression models were constructed in order to assess the contribution of homozygous or heterozygous variant genotypes of polymorphisms MMP-1 (-1607 1G/2G), MMP-3 (-1171 5A/6A), MMP-9 (-1562C/T), TIMP-2 (-418C/G), VEGF (+936C/T), GPI-alpha (+807C/T), PAI-1 (4G/5G), ACE (intron 16D/I) and TAFI (+325C/T) upon overall, early and advanced stages of OSCC. Four out of nine polymorphisms affecting PAI-1, MMP-9, TIMP-2 and ACE expression contributed significantly in OSCC prediction in the various logistic regression models. Based on these findings and previous reports, possible interactions of the implicated factors leading to OSCC development, as well as an algorithm of risk estimation are discussed.

Oestrogen treatment of constitutional tall stature in girls: is there a risk of thrombosis or bleeding?

AIM: To evaluate haemostatic effects and clinical outcome of oestrogen treatment of constitutionally tall stature in girls. METHODS: We conducted a single-centre cohort study, 63 girls referred over a period of 15 years were investigated. The girls were given oestrogen treatment for constitutional tall stature at a median initial dose of 300 ug ethinyl estradiol/day and were consecutively examined for changes in coagulation. Medical records were retrospectively reviewed, additional data were collected at follow-up by blood sampling and interviews. RESULTS: After 1 year of treatment, levels of antithrombin and von Willebrand factor (VWF) were significantly decreased (p<0.001 and p=0.015, respectively), whereas there was no significant change in levels of plasminogen inhibitor type 1. No venous thromboembolism (VTE) or major side effects were observed. Genetic risk factors for thrombosis were present, as was expected. The mean height reduction was 5.5 cm. The height-reducing effect was inversely correlated with chronological age (r=-0.44, p<0.01) and bone age (r=-0.61, p<0.01). CONCLUSIONS: Changes in coagulation parameters occurred both towards pro- and anticoagulation. Treatment with high-dose ethinyl estradiol can successfully limit final height, and it is most effective when started at a younger bone age.

Insulin resistance, obesity, hypofibrinolysis, hyperandrogenism, and coronary heart disease risk factors in 25 pre-perimenarchal girls age < or =14 years, 13 with precocious puberty, 23 with a first-degree relative with polycystic ovary syndrome.

BACKGROUND: Pre-peri-menarchal diagnosis of polycystic ovary syndrome (PCOS) is important, because intervention with metformin-diet may prevent progression to full blown PCOS. HYPOTHESIS: In 25 girls age < or =14 years with probable familial PCOS, 10 pre-, 15 post-menarchal, 13 with precocious puberty, 23 with a first-degree relative with PCOS, we hypothesized that reversible coronary heart disease (CHD) risk factors, insulin resistance, clinical and biochemical hyperandrogenism, and hypofibrinolysis were already established. METHODS: Fasting measures: insulin, glucose, total, LDL- (LDL-C), and HDL-cholesterol (HDL-C), triglycerides (TG), systolic and diastolic blood pressure (SBP, DBP), plasminogen activator inhibitor activity (PAI-Fx), total (T) and free testosterone (FT), androstenedione, and DHEAS. RESULTS: Clinical and/or biochemical hyperandrogenism was present in all 25 girls, with elevations of T or FT, or androstenedione in seven of ten pre-menarchal girls and in all 15 post-menarche. PAI-Fx was high in 28% of the 25 girls vs 6.5% in age-gender-race matched controls (p = 0.013). Categorized by race-age-specific distributions in 870 schoolgirls, the 25 girls with probable familial PCOS were more likely to have top decile body mass index (BMI), insulin, HOMA-insulin resistance (HOMA-IR), SBP, DBP, and TG, and bottom decile HDL-C. By analysis of variance, adjusting for race, age and BMI, PCOS girls had higher FT and waist circumference than controls, but did not differ for SBP, DBP, HDL-C, or TG (p>0.05). CONCLUSIONS: Pre-peri-menarchal acquisition of centripetal obesity amplifies CHD risk factors and hypofibrinolysis in hyperandrogenemic girls with probable familial PCOS and precocious puberty. When schoolgirls become as obese as girls with probable familial PCOS, they acquire the same CHD risk factors, and differ only by lower free T and less centripetal obesity.

Coagulation activation and organ dysfunction following cardiac surgery.

STUDY OBJECTIVES: Cardiac surgery with cardiopulmonary bypass (CPB) is associated with major inflammatory triggers that cause marked activation of the microcirculation. This inflammatory response is associated with significant organ dysfunction. How this response causes organ dysfunction is not well understood; consequently, few interventions exist to prevent or treat it. In other acute inflammatory conditions, such as sepsis, increased coagulation activation in the microcirculation may be a cause of organ injury. We documented the association between coagulation activation and organ dysfunction to investigate whether coagulation activation also plays a role in organ injury following cardiac surgery with CPB. DESIGN: Prospective study of 30 patients undergoing cardiac surgery with CPB. Prothrombin fragment (PTF) 1 + 2 and plasminogen activator inhibitor (PAI) activity were measured, and levels correlated with postoperative measures of organ function including the left-ventricular stroke work index, the Pao(2)/fraction of inspired oxygen (Fio(2)) ratio, and creatinine levels. RESULTS: PTF levels increased eightfold (p < 0.05), and PAI activity increased threefold (p < 0.05) over the first 4 h after CPB. PTF levels were correlated with deteriorations in the left-ventricular stroke work index (p = 0.04), the Pao(2)/Fio(2) ratio (p = 0.02), and creatinine levels (p = 0.02). CONCLUSIONS: Levels of coagulation activation are associated with markers of postoperative organ dysfunction. Additional studies are warranted to investigate whether strategies that limit coagulation activation are associated with reductions in postoperative organ dysfunction.

[Thrombotic, fibrinolytic and proliferative activities of pulmonary vascular bed in secondary pulmonary hypertension]. / Sekonder pulmoner hipertansiyonda pulmoner vasküler yatagin trombotik, fibrinolitik ve proliferatif aktiviteleri.

OBJECTIVE: To determine whether pulmonary vascular bed contributes to the development of in situ thrombosis and vascular remodelling in secondary pulmonary hypertension (SPH) via changes in its local secretory activities. METHODS: Seventy-one patients with the diagnosis of secondary pulmonary hypertension (38 females, mean age 40.36+/-1.05 years) were included in the study. Selective right and left heart catheterization was performed to each patient for diagnostic purposes. Blood samples obtained from left ventricle (LV) and pulmonary artery (PA) of each patient were analyzed for levels of plasminogen activator inhibitor-1 (PAI-1), platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF), D-dimer, von Willebrand factor (vWF), protein-C, antithrombin-III, fibrinogen, and plasminogen. Results were compared between LV and PA. Correlation analysis between each parameter and mean pulmonary artery pressure (MPAP) was performed. RESULTS: Although mean level of VEGF in LV and PA were found to be in normal range, it was significantly higher in LV than in PA (p<0.001). Mean PDGF and D-dimer levels, which remained in normal range were also higher in LV (p<0.001 and p<0.001, respectively) than in PA;.vWF showed similar degree of elevation in both LV and PA. Only one parameter, PAI-1, was found to be significantly higher in PA than in LV (p=0.012). Antithrombin-III, protein C, plasminogen, and fibrinogen levels showed no significant differences between two chambers. They also remained in normal range, except for fibrinogen, which was slightly elevated in both LV and PA. Correlation analysis revealed strong positive correlation between D-dimer level in both LV and PA and MPAP (r=0.775, p<0.001 and r=0.649, p<0.001, respectively). CONCLUSION: In SPH, pulmonary vascular bed shows increased thrombotic, hypofibrinolytic, and proliferative activities, which are partially related to the severity of illness.

Plasminogen activator system in smokers and non-smokers with and without periodontal disease.

BACKGROUND: The present study assessed levels of plasminogen activator (PA) system proteins in gingival crevicular fluid (GCF) and serum of chronic gingivitis, chronic periodontitis patients and periodontally healthy subjects and evaluated how smoking influenced these levels. METHODS: Twenty chronic gingivitis; 20 chronic periodontitis patients and 20 periodontally healthy volunteers were consecutively recruited according to the inclusion criteria so that exactly half of the subjects in each category were smokers. GCF samples from four sites together with serum samples were obtained from each subject. GCF levels of tissue type PA (t-PA), urokinase type PA (u-PA), PA inhibitor-1 (PAI-1) and PA inhibitor-2 (PAI-2) and serum concentrations of cotinine, u-PA and PAI-1 were analysed by enzyme-linked immunosorbent assay. RESULTS: The only statistically significant difference between smokers and non-smokers was a lower GCF PAI-2 concentrations in healthy smokers compared with healthy non-smokers (p<0.01). Gingivitis and periodontitis patients had higher GCF concentrations of PAI-2 than healthy subjects (p<0.002 and p<0.02 respectively). The ratio of u-PA:PAI-1 and t-PA:PAI-1 were significantly higher in GCF of smokers with periodontitis compared with "healthy" smokers, whereas the ratio of t-PA:PAI-2 was significantly lower in smokers with periodontal disease (p<0.05). CONCLUSIONS: GCF levels of the PA system proteins are increased in chronic gingivitis and periodontitis compared with healthy gingiva. Smoking had only subtle effects on the GCF PA system proteins with the exception of PAI-2, and the balance of activators and inhibitors. These findings suggest one mechanism whereby smoking may exert detrimental effects on the periodontal tissues.

[Incidence of deep venous thrombosis (DVT) in patients undergoing thoracotomy and changes of hemostasis].

OBJECTIVE: To survey the incidence of deep venous thrombosis (DVT) in high risk patients undergoing thoracotomy and observe the changes of hemostatic activity. METHODS: Fifty-two consecutive patients (ages that ranged from 35 to 79, 34 men and 18 women) with lung or esophagus cancer were enrolled into this prospective trial. The patients included underwent major thoracic surgery from February 2003 to April 2003. Bilateral lower extremity duplex ultrasonography for DVT screening was performed 3-10 days post surgery in all 52 patients and 57 matched clinic normal controls. Venous blood was collected to determine fibrinogen (FIB), D-dimer(D-D), plasminogen activator inhibitor (PAI), antithrombin (AT)i thrombin antithrombin complex (TAT), prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (APTT) immediately before surgery, the third and tenth days postoperatively. No patient had a prior thromboembotic history. Risk factors for DVT were evaluated. RESULTS: Of the 52 patients, 28 (53.8%) had an acute postoperative DVT detected in the calf. One patient died of suspected pulmonary embolism postoperatively. Plasma levels of FIB and D-D increased significantly up to 7 d after operation. AT level decreased significantly 3 d after operation and returned to normal 7 d latter. TAT increased significantly 3 d post operation and decreased to normal on day 7. PAI level was lowered 3 d after surgery, but increased significantly on day 7 compared with that on day 3. With the addition of risk factors related to thrombosis, the incidence of DVT was increased correspondingly. CONCLUSION: Of the patients undergoing major thoracic surgery,53.8% of them had a postoperative DVT by postoperative screening duplex ultrasound. In Chinese population, incidence of DVT appears to be high without prophylaxis, which is similar to other reports of westerners. These patients had a number of risk factors for the development of DVT, which include older age, overweight, hypertension, diabetes, and history of thromboembolism, etc. Prophylactic measures should be taken against postoperative venous thromboembolism in major thoracic surgery with high risk, including early mobilization, anticoagulant therapy with heparins, and intermittent pneumatic compression (IPC).

Obstructive sleep apnea and cardiovascular disease.

Obstructive sleep apnea (OSA) is a common medical condition that occurs in approximately 5% to 15% of the population. The pathophysiology of OSA is characterized by repetitive occlusions of the posterior pharynx during sleep that obstruct the airway, followed by oxyhemoglobin desaturation, persistent inspiratory efforts against the occluded airway, and termination by arousal from sleep. Obstructive sleep apnea is associated with daytime sleepiness and fatigue, likely due to fragmented sleep from recurrent arousals. Substantial evidence shows that patients with OSA have an increased incidence of hypertension compared with individuals without OSA and that OSA is a risk factor for the development of hypertension. Recent studies show that OSA may be implicated in stroke and transient ischemic attacks. Obstructive sleep apnea appears to be associated with coronary heart disease, heart failure, and cardiac arrhythmias. Pulmonary hypertension may be associated with OSA, especially in patients with preexisting pulmonary disease. Although the exact cause that links OSA with cardiovascular disease is unknown, there is evidence that OSA is associated with a group of proinflammatory and prothrombotic factors that have been identified to be important in the development of atherosclerosis. Obstructive sleep apnea is associated with increased daytime and nocturnal sympathetic activity. Autonomic abnormalities seen in patients with OSA include increased resting heart rate, decreased R-R interval variability, and increased blood pressure variability. Both atherosclerosis and OSA are associated with endothelial dysfunction, increased C-reactive protein, interleukin 6, fibrinogen, and plasminogen activator inhibitor, and reduced fibrinolytic activity. Obstructive sleep apnea has been associated with enhanced platelet activity and aggregation. Leukocyte adhesion and accumulation on endothelial cells are common in both OSA and atherosclerosis. Clinicians should be aware that OSA may be a risk factor for the development of cardiovascular disease.

Effect of four oral contraceptives on hemostatic parameters.

This is the first double-blind, controlled, randomized study comparing the effect of different estrogen components in oral contraceptives (OCs) on hemostasis variables. Four groups of 25 women each were treated for six cycles with monophasic combinations containing 21 tablets with either 30 microg ethinylestradiol (EE) + 2 mg dienogest (DNG) (30EE/DNG), 20 microg EE + 2 mg DNG (20EE/DNG), 10 microg EE + 2 mg estradiol valerate (EV) + 2 mg DNG (EE/EV/DNG) or 20 microg EE + 100 microg levonorgestrel (LNG) (EE/LNG). Blood samples were taken on Days 21-26 of the control cycle and on Days 18-21 of the first, third and sixth treatment cycle. Treatment with all four OCs caused an increase in levels of fibrinogen, prothrombin fragment 1+2, D-dimer, plasminogen, plasmin-antiplasmin complex and an increase in protein C activity, a decrease in antithrombin activity, tissue-plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI), and a slight decrease in the sensitivity to activated protein C, but no significant change in that of the thrombin-antithrombin complex. In users of the DNG-containing OCs, the reduction in total and free protein S, and in t-PA and PAI was dependent on the EE dose, while factor VII activity was elevated, but not significantly different from EE/LNG. The results are in agreement with those of previous studies. The effects of EE/EV/DNG on total and free protein S and on t-PA and PAI were lower than those of 20EE/DNG, suggesting that the impact of 2 mg EV on several hemostasis variables is less than that of 10 microg EE. The results show an antagonistic effect of LNG on the EE-induced rise of factor VII activity and fragment 1+2 and on the EE-dependent reduction of total and free protein S.

Metformin during pregnancy reduces insulin, insulin resistance, insulin secretion, weight, testosterone and development of gestational diabetes: prospective longitudinal assessment of women with polycystic ovary syndrome from preconception throughout pregnancy.

BACKGROUND: In a prospective observational study of 42 pregnancies in 39 Caucasian women (age 30 +/- 4 years) with polycystic ovary syndrome (PCOS), we examined effects of metformin on maternal insulin, insulin resistance (IR), insulin secretion (IS), weight gain, development of gestational diabetes (GD), testosterone and plasminogen activator inhibitor activity. We assessed the hypothesis that diet-metformin (MET) lessens the physiological gestational increase in IR and reduces gestational weight gain, thus reducing GD. METHODS: Preconception, in an out-patient clinical research centre, MET 1.5 (eight pregnancies) to 2.55 g/day (34 pregnancies) was started. Women with body mass index <25 or >or=25 kg/m(2) were given a 2000 or 1500 calorie/day, high-protein (26% of calories), low-carbohydrate (44%) diet. Calorie restrictions were dropped after conception. RESULTS: On MET, GD developed in three out of 42 pregnancies (7.1%). Median entry weight (94.5 kg) fell to 82.7 on MET at the last preconception visit (P = 0.0001), fell further to 81.6 during the first trimester, was 83.6 in the second trimester, and 89.1 kg in the third trimester. Median weight gain during pregnancy was 3.5 kg. The median percentage reduction in serum insulin was 40% on MET at the last preconception visit; insulin did not increase in the first or second trimesters (P > 0.05), and rose 10% in the third trimester. The median percentage reduction in HOMA IR was 46% on MET at the last preconception visit; IR did not increase (P > 0.05) in the first, second or third trimesters. HOMA insulin secretion fell 45% on MET at the last preconception visit, did not increase in the first trimester, rose 24% in the second trimester, and rose 109% in the third trimester. Testosterone fell 30% on MET at the last preconception visit (P = 0.01) and then rose 74, 61 and 95% during trimesters 1, 2 and 3; median testosterone during the third trimester did not differ from pre-treatment levels. CONCLUSIONS: By reducing preconception weight, insulin, IR, insulin secretion and testosterone, and by maintaining these insulin-sensitizing effects throughout pregnancy, MET-diet reduces the likelihood of developing GD, and prevents androgen excess for the fetus.

New data on chemotherapy in the adjuvant setting.

In the last few months, there have been three sets of new, provocative data that might have important implications for the daily prescription of adjuvant chemotherapy (CT) in the future. (1) Urokinase-type plasminogen activator (UPA) and type 1 plasminogen activator inhibitor (PAI-1), two molecular markers of invasion already known for their powerful prognostic value in node-negative breast cancer, seem to predict for enhanced benefit from adjuvant CT, while the benefit from adjuvant endocrine therapy seems independent of them. The predictive value of these markers, however, remains suboptimal and an important limitation lies in their evaluation through a cytosolic assay, which is compromised for small tumours (<1cm). (2) Breast cancer 'gene expression profiles' have been identified through DNA-microarray technology and seem to be better predictors of clinical outcome in young women (less than 55 years old) with stage I or II breast cancer, when compared to the currently used clinical-pathological criteria. Remarkably, these molecular data suggest that the prognostic profile of breast cancer does not depend on lymph node status and that it is possible to identify a group of node-positive breast cancer patients with an unexpectedly good prognosis. Prospective and independent confirmation is needed, but these data are fascinating and carry the hope that CT decision-making in breast cancer will be greatly facilitated in the future. (3) The recently reported CALGB 9741 (or INT 69741) trial shakes our belief that 'one cycle of CT every 3 weeks' is the adequate adjuvant treatment for node-positive breast cancer. Launched in 1999, it aimed to test two novel concepts based on mathematical models of tumour cell growth kinetics. Concept 1 implies that dose-densification of CT, i.e., delivering drugs at reduced intervals, will maximize the chances of eradicating the tumour; and concept 2 extends the first one to encompass situations of heterogeneous drug sensitivity through the use of sequential dose-dense, non-cross-resistant single agents or regimens. The 3-year results of this trial strongly support concept 1; a longer follow-up and a confirmation study are desirable before recommending changes in routine patient care.

Comparative study of the effects of two once-a-month injectable contraceptives (Cyclofem and Mesigyna) and one oral contraceptive (Ortho-Novum 1/35) on coagulation and fibrinolysis.

A randomized controlled multicenter study was undertaken to monitor the effects on hemostasis of two once-a-month injectable contraceptive preparations, Mesigyna (50 mg norethisterone enanthate and 5 mg estradiol valerate) and Cyclofem (25 mg medroxyprogesterone acetate and 5 mg estradiol cypionate) in comparison with a well-known oral contraceptive (OC) Ortho-Novum 1/35 (norethisterone 1 mg and ethinyl estradiol 35 microg). A total of 378 volunteers from four centers (Bangkok, Hangzhou, Santiago and Singapore) were monitored. Blood sampling took place in one pretreatment cycle, the third and ninth injection intervals and one posttreatment cycle. In each of the three treatment groups, a rise in hemoglobin, and increases in platelet count and in prothrombin time were observed. With treatment there was a significant increase in activated partial thromboplastin time among Mesigyna users, no change among Cyclofem users and a significant decrease among OC users. OC use led to increases in plasma levels of fibrinogen, factor VII, factor X, plasminogen, protein C and decreases in plasma levels of t-PAI and antithrombin. Use of combined injectables induced no change (Cyclofem) or decreases (Mesigyna) in plasma levels of fibrinogen, factor VII, factor X and antithrombin. Use of both combined injectables led to decreases in protein C, slight decreases in plasminogen and increases in plasminogen and fibrinogen. Overall, the injectable preparations may be more beneficial than the oral preparation in not enhancing a hypercoagulable state because of the reduced synthesis of fibrinogen, factors VII and X; however, decreases in antithrombin and protein C, which are potent coagulation inhibitors, may raise some concern. Whether these changes can lead to modifications in the risk of arterial or venous disease can only be ascertained by conducting epidemiological studies.

Effects of octreotide on epidermal growth factor receptor, tissue plasminogen activator, and plasminogen activator inhibitor during intraperitoneal adhesion formation.

BACKGROUND: Intraperitoneal adhesions remain a problem after abdominal surgery. Octreotide has been proved to be able to reduce the number, strength, and extent of fibrous bands at and away from the anastomotic site in an animal model of rats with intestinal resection and reanastomosis. The aim of the present study was to investigate whether epidermal growth factor receptor (EGF-R), tissue plasminogen activator (tPA), and plasminogen activator inhibitor (PAI) are involved in this process. METHODS: Laparotomy with intestinal resection and reanastomosis was performed on 60 male Wistar rats. All rats were randomly assigned to five groups: receiving no medication (control; C), normal saline (NS), octreotide solution peritoneal irrigation (Oc), octreotide intramuscular injection (IM), and Oc plus octreotide intramuscular injection (Oc + IM). The concentrations of serum EGF-R, plasma tPA, PAI-1, and PAI-2, and the strength of wound healing were measured. RESULTS: The serum EGF-R concentration showed no significant change from the preoperative level in the C and NS groups 7 and 14 days after the abdominal surgery. However, it decreased significantly on postoperative days 7 and 14 in groups Oc, IM, and Oc + IM ( P < 0.05). The plasma tPA concentrations were significantly higher than the preoperative level in all groups of rats on postoperative day 7. The levels were higher in groups Oc, IM, and Oc + IM than in group C or group NS at that time ( P < 0.05). On postoperative day 14, the plasma tPA concentrations had returned to the preoperative level in group C and group NS. However, the concentrations in groups Oc, IM, and Oc + IM still remained at a significantly higher level than the concentrations in group C and group NS. The plasma PAI-1 and PAI-2 concentrations showed no significant difference from the preoperative level in group C and group NS on days 7 and 14 after the abdominal surgery. However, the concentrations in groups Oc, IM, and Oc + IM on postoperative days 7 and 14 were markedly lower than those in groups C and NS ( P < 0.05). The wound strength was significantly greater on day 14 than on day 7 in all groups. CONCLUSIONS: In the rats with octreotide irrigation, the EGF-R level was decreased, the plasma tPA concentration was higher, and the plasma PAI-1 and PAI-2 concentrations were lower when compared with values in group C and group NS rats on days 7 and 14 after surgery. The data suggest that EGF-R, tPA, PAI-1, and PAI-2 are all involved in the mechanism of octreotide's action in reducing adhesion formation.