Effect of gemfibrozil on serum lipids in man

The effect of gemfibrozil, a new lipid-lowering agent, was studied in 22 patients. Each patient served as his own control in a double blind study. The administration of gemfibrozil, for a period of 24 months, 1200 mg daily, reduced mean serum triglyceride levels by 45.6% (p less than 0.001) and mean serum cholesterol levels by 8.3% (p less than 0.001). Mean serum HDL cholesterol was increased by 32.3% (p less than .0001) and mean serum LDL cholesterol levels were decreased by 11.4% (p less than 0.01). Mean serum VLDL cholesterol was decreased by 45.9% (p less than 0.001). A 3-hour glucose-tolerance test was done in each patient during a placebo-control period and during the administration of gemfibrozil. Mean plasma glucose was moderately increased during the administration of gemfibrozil at all points on the glucose tolerance curve, and to levels of significance at one (p less than 0.05) and two hours (p less than 0.02). There was no effect of the drug on serum immunoreactive insulin. No subjective side effects were apparent.     

Phospholipids accelerate factor IX activation by surface bound factor XIa

Activation of bovine factor IX by surface bound factor XIa which was generated either by activation of human citrated factor IX deficient plasma or a mixture of purified human factors XII, high molecular weight kininogen (HMWK) and XI in glass tubes, is accelerated by cephalin. Human brain cephalin in dilutions ranging from 1:5 to 1:500 was studied for its effect on the activation of factor IX in concentrations of 1.0 u/ml and 16 u/ml. Cephalin dilutions from 1:5 to 1:30 accelerated the activation of the concentrated factor IX sample two- to threefold. Protein cleavage of this factor IX sample in the presence of 1:30 cephalin occurred twice as fast as in the absence of cephalin. Activation of the dilute factor IX sample (1.0 u/ml) was most effectively accelerated by cephalin in dilutions from 1:30 to 1:250. In all experiments the presence of phospholipid led to an increased factor IX cleavage concomitantly with faster generation of factor IXa activity. The results demonstrate that phospholipids actively participate in blood coagulation at an earlier stage than previously described.     

Evidence for abnormal granulosa cell responsiveness to follicle-stimulating hormone in women with polycystic ovary syndrome

Women with polycystic ovary syndrome (PCOS) undergoing ovulation induction appear to be extremely sensitive to gonadotropin stimulation and at increased risk for ovarian hyperstimulation syndrome. To determine granulosa cell responsiveness to recombinant human FSH (r-hFSH), dose-response studies were conducted in 16 individual PCOS patients and 7 normal women. Each subject received an iv injection of r-hFSH at doses of 0, 37.5, 75, or 150 IU in a randomized fashion on four separate occasions. Blood samples were obtained at frequent intervals before and for 24 h after r-hFSH administration for measurement of gonadotropins and steroid hormones. Our results showed that administration of r-hFSH produced instantaneous and equivalent dose-related increases in serum FSH in PCOS and normal women, which were followed by similar exponential decreases to baseline levels within 24 h in both groups. In PCOS subjects, the peak mean incremental response of serum estradiol (E(2)) to 150 IU of r-hFSH was 1.8-fold greater (P < 0.0001) and considerably accelerated compared with that found in normal women. In contrast, E(2) responses to 37.5 IU and 75 IU were similar between groups. Regression analysis of maximal E(2) concentrations in response to r-hFSH in each individual subject revealed that the slope of the linear trend line in the group of women with PCOS (r = 0.82) was significantly greater (P < 0.01) than that of normal controls (r = 0.71). The time-course of response revealed that in PCOS women, increases of E(2) were not sustained, compared with those of normal controls, because peak concentrations were followed by an estimated 40% decrement in circulating levels, whereas E(2) levels in normal women persisted for 24 h after reaching maximal values. These findings indicate that women with PCOS exhibit a significantly greater capacity for E(2) production in response to iv r-hFSH, compared with normal women. In PCOS, E(2) production was relatively transient because after peak concentrations a marked decline was detected at each dose, unlike normal women who exhibited persistent elevations of E(2) for up to 24 h. That this distinction was dose-dependent supports the concept of an FSH dose-response threshold, beyond which PCOS but not normal women are susceptible to ovarian hyperresponsiveness.     

Multiple anomalous venous systemic connections in a case of atrial septal defect associated with right aortic arch and spine defromities

Multiple anomalies of persistent left superior vena cava and left hepatic vein emptying into the left atrium associated with atrial septal defect, right aortic arch and multiple skeletal malformations are presented. The anatomy and the embryology of these anomalous venous connections are briefly reviewed. Clinical, hemodynamic and surgical implications of these anomalies are discussed.     

The Influence of Different Cultivating Conditions on Polymorphonuclear Leukocyte Apoptotic Process In Vitro,II: Ultrastructural Characteristics of PMN Populations Incubated with Proteinase 3 Anti-neutrophil Autoantibodies

The present study shows the effects of proteinase 3 anti-neutrophil cytoplasmic autoantibodies (PR3 ANCA) on polymorphonuclear leukocytes (PMN) apoptotic processes in vitro. The results are part of a generalized morphological analysis of 3 identical experiments on the influence of different cultivating conditions on the apoptotic processes. As controls, the authors use the results on spontaneous PMN apoptosis (Guejes L, Zurgil N, Deutsch M, Gilburd B, Shoenfeld Y. Ultrastruct Pathol. 2003;27:23–32) and PMN populations incubated with normal human IgG. Interaction of PR3 ANCA with the target antigen proteinase 3 (PR3) is one of the crucial pathogenic factors in Wegener granulomatosis (systemic autoimmune vasculitis). Following 40 min and 12 h incubation, PMN populations were evaluated by light microscopy, transmission electron microscopy, and immunogold electron microscopy. Twelve-hour cultures, either control or incubated with PR3 ANCA, contained different cell forms ranging from normal cells to cells at the final stages of apoptosis. Neutrophils at the state of complete manifestation of apoptotic phenotype were analyzed and compared. Three morphologically distinct apoptotic cell lines were characteristic for all PMN populations studied, regardless of cultivating conditions. As in spontaneous apoptosis, these cell lines are code-named “first,” “second,” and “third.” The present study has shown, firstly, that in the presence of PR3 ANCA, all 3 apoptotic lines were modified or altered. Secondly, the modifications or alterations of apoptotic cell lines effected by PR3 ANCA are specific for each cell line: the “first” line is characterized by intensification and modification of activation; the “second” by vacuolized cell forms; and the “third” by pronounced lytic alterations of the nuclei, while the cytoplasm is fully identical to that of control cell lines.     

A Thrombus Susceptibility Comparison of Two Pulsatile Penn State 50?cc Left Ventricular Assist Device Designs

Left ventricular assist devices (LVADs) have proven successful as bridge to transplant devices for patients awaiting donor organs. While survival rates continue to increase, destination therapy remains hindered by thrombus formation within the device. Research has shown that thrombosis is correlated to the fluid dynamics within the device and may be a result of sustained shear rates below 500?s^?1 on the polyurethane blood sac used in the Penn State pulsatile LVAD. Particle image velocimetry is used to compare flow within two 50?cc LVAD designs to assess fluid patterns and quantify wall shear rates in regions known from in vivo studies to be susceptible to thrombus formation. The two designs differ in their front face geometry. The V-1 model has an outward-facing ??dome?? whereas the face of the V-2 model is flat. A thrombus susceptibility metric, which uses measured wall shear rates and exposure times, was applied to objectively compare pump designs over the entire cardiac cycle. For each design, there are regions where wall shear rates remained below 500?s^?1 for the entire cardiac cycle resulting in high thrombus susceptibility potential. Results of this study indicate that the V-2 device had an overall lower propensity for thrombus formation in the current region of interest.     

Platinum-resistance in ovarian cancer cells is mediated by IL-6 secretion via the increased expression of its target cIAP-2

Ovarian carcinoma patients are initially responsive to platinum-based therapy, but eventually become refractory to treatment due to the development of platinum chemoresistance. Elevated levels of interleukin-6 (IL-6) in the sera and ascites of these patients predict poor clinical outcome. Our goal was to analyze the interaction between cisplatin and cisplatin-resistant ovarian cancer cells, and to identify means of circumventing platinum resistance. We studied ovarian carcinoma cell lines and cells drawn from ovarian carcinoma patients. Gene array analyses were performed on ovarian carcinoma cells upon treatment with cisplatin, and the results were validated by ELISA and Western blotting (WB). Cytotoxicity assays were performed on anti-IL-6 Ab-, IL-6-, and cellular inhibitor of apoptosis 2 (cIAP-2) siRNA-treated cells, following cisplatin addition. Our results revealed a highly significant increase in IL-6 and cIAP-2 mRNA and protein levels upon treatment with cisplatin. WB analysis of cisplatin-treated cells exhibited decreased cIAP-2 expression level following anti-IL-6 Ab addition. Furthermore, IL-6 by itself, significantly increased cIAP-2 levels in ovarian carcinoma cells. Finally, cytotoxicity assays showed sensitization to cisplatin following the addition of IL-6 and cIAP-2 inhibitors. In conclusion, cisplatin treatment of ovarian carcinoma cells upregulates IL-6 and cIAP-2 levels while their inhibition significantly sensitizes them to cisplatin. Here, we present cIAP-2 as a novel inducer of platinum resistance in ovarian carcinoma cells, and suggest an axis beginning with an encounter between cisplatin and these cells, mediated sequentially by IL-6 and cIAP-2, resulting in cisplatin resistance. Consequently, we propose that combining IL-6/cIAP-2 inhibitors with cisplatin will provide new hope for ovarian carcinoma patients by improving the current treatment.     

Relative bioavailability and antioxidant potential of two coenzyme q10 preparations

Coenzyme Q10 (CoQ10) is synthesized by the human body and found in certain foods. Daily supplementation of CoQ10 could protect against heart disease but the bioavailability of CoQ10 supplements depends on the formulation taken. We compared the bioavailability and antioxidant properties of two commercial CoQ10 formulations, a commercial grade CoQ10 powder (commercial grade CoQ) and a new BT-CoQ10 BIO-TRANSFORMED (BT-CoQ10) obtained by fermentation of a soy-based, CoQ10-rich media with baker's yeast. Eleven healthy individuals participated in a randomized two-way crossover trial, with a 3-week washout period. Capsules containing 300 mg of either BT-CoQ10 or commercial grade CoQ10 were given daily for 1 week and multiple blood samples were taken for CoQ10, glutathione and glutathione peroxidase (GPx) determination. In 3 subjects, baseline plasma CoQ10 levels were lower prior to BT than prior to commercial grade CoQ treatment. In the remaining participants, ingestion of BT vs. commercial grade CoQ significantly increased maximum plasma CoQ10 concentration (+126%, p = 0.04) and tended to increase CoQ10 area under the curve from 0 to 24 h (+160%, p = 0.07). One week of treatment with each formulation increased plasma CoQ10 but did not alter plasma glutathione or GPx activity. The enhanced bioavailability of the BT product might be due to its predominantly reduced, hydrophilic membrane-complex form.