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The role of bladder stretching in maintaining bladder health: plasma cytokine levels in catheterised patients using valves or continuous drainage
No full textDoes human semen contain a functional haemostatic system? a possible role for tissue factor pathway inhibitor in fertility through semen liquefaction
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Quantitation of seminal Factor IX and Factor IXa in fertile, non-fertile and vasectomy subjects: a step closer towards identifying a functional clotting system in human semen
No full textCoagulation factor (F) IX is a zymogen of the plasma serine proteases, one that plays an essential role in the regulation of normal blood coagulation. Congenital defects of FIX synthesis or function cause hemophilia B (originally called hemophilia C). Factor IX is activated by Tissue Factor (TF):FVII/FVIIa complex and FXIa. Subsequent to its activation, FIXa combines with FVIIIa on the platelet surface and activates FX to FXa. Human semen forms a semi-solid gelatinous coagulum, which then liquefies within 5-20 minutes in vitro. In spite of evidence demonstrating the importance of the seminal coagulation and liquefaction process in terms of global fertility and despite the fact that the seminal coagulum is composed of fibrin-like material, it has always been addressed from the perspective of High Molecular Weight Seminal Vesicle (HMW-SV) proteins (Semenogelin I and II) and their cleavage by prostate-specific antigen rather than the conventional hemostatic factors. In this study and as part of our continuing investigation of human seminal clotting factors, we report here on seminal FIX and FIXa in normal, subfertile, and vasectomized subjects. Factors IX and FIXa were studied in a total of 119 semen specimens obtained from subfertile (n = 18), normally fertile (n = 34), and fertile sperm donors (n = 27) and vasectomy subjects (n = 40). Seminal FIX and FIXa levels were also measured in a group defined by normality in several parameters derived from the World Health Organization fertility criteria and termed "pooled normal semen parameters." Both FIX and FIXa were quantifiable in human semen. There was a wide individual variation in FIX and FIXa levels within groups. Despite the group size, statistically significant associations with fertility-related parameters were infrequent. There is a positive correlation between FIX and its activation product, FIXa (n = 36; r = 0.51; P < .05). Factor IXa elevation in the high sperm-clump group was significant (P < .05), and days of abstention correlated with FIXa levels (n = 63; r = 0.3; P < .05). The key finding of the present study is that both FIX and FIXa are present in concentrations that are not dissimilar to plasma levels and that are apparently functional, as the activated form is also present. This fact, taken with other reports of coagulation factors in semen, raises the likelihood that a functional set of hemostatic coagulation proteins exists in semen, potentially to interact with the HMW-SV proteins and the prostate-specific antigen system
Seminal clotting and fibrinolytic balance: A possible physiological role in the male reproductive system
No full textSemen contains enzymes and inhibitors of the haemostatic system as well as the high molecular weight seminal vesicle (HMW-SV) proteins. The former may have roles in seminal clotting and in liquefaction through “fibrinolytic” activity, which may ultimately affect fertility. Although a limited number of studies have addressed the subject, the role of clotting and fibrinolytic factors in semen remains poorly understood. The liquefaction time and the distribution of components vary across split ejaculates. This may have an important bearing on the way clotting/fibrinolytic factors in semen are assessed. Semen contains tissue factor (TF, Thromboplastin, CD142), which originates from the prostate and is associated with prostasomes. The function of TF (and prostasomes) in semen is still a matter for speculation. Recently the presence of minute amounts of factor VII in semen has been demonstrated but its importance is uncertain. Semen also contains a thrombin-like enzyme, prothrombin fragments 1 and 2 (F1+2), D-dimer (DD) and thrombin-antithrombin (TAT) complexes. The presence of several fibrinolytic factors has been demonstrated in semen but few questions about their potential impact on semen quality have been raised. Factors found include tissue plasminogen activator (t-PA), urinary plasminogen activator (u-PA) and plasmin.There are also traces of fibrinogen, plasminogen, plasminogen activator inhibitor-1 (PAI-1), factor VIII coagulant activity (VIII:c) and fibrin monomers.The co-ordinate expression of both TF and PAI-1 by decidual cells of the endometrium is believed to be important in maintaining haemostasis during endovascular trophoblast invasion. Kallikrein-like serine protease inhibitors including prostate specific antigen (PSA) are known to be present in semen at high concentrations. In semen PSA is also found in a complex form with protein C inhibitor (PCI) with mutually inhibitory consequences. A better understanding of the spectrum of coagulating and liquefaction agents in semen to include classical haemostatic processes and the pathogenesis resulting from any imbalances between or within either system may provide the basis for the development of more selective and efficient agents affecting global fertility. Here we review aspects of male reproductive physiology in the light of recent findings concerning conventional clotting/fibrinolytic systems in human semen with a view to stimulating further research
Does human semen contain a functional haemostatic system?
No full textThere is already evidence that a few components of the haemostatic system exist in semen. If these comprise a functional system, they may have a role in seminal clotting and liquefaction processes and ultimately may influence fertility. What might be expected in semen as collected from fertility clinics i.e., after having both coagulated and subsequently liquefied is uncertain. It does however still contain significant amounts of Tissue Factor (TF) although its effect on semen quality remains poorly understood. The present study analyses semen for Tissue Factor Pathway Inhibitor (TFPI). Measurements were made in seminal plasma, swim-up sperm and prostasomes and its relationship with conventional fertility parameters assessed. TFPI antigen levels in seminal plasma were measured in a total of 176 subjects using an Enzyme-linked immunosorbent assay (ELISA). These include sub-fertile (n=37), normally fertile (n=40), fertile sperm donor (n=34), vasectomized subjects (n=65) and in a further group de- fined by normality in several parameters derived from the World Health Organization (WHO) fertility criteria and termed “pooled normal semen parameters” (PNSP). For characterization studies, both TFPI activity and antigen were measured on whole semen, swim-up sperm and prostasome-rich fraction (n=5). TFPI levels were significantly higher in normal men as compared to sub-fertile ( P <0.01) or vasectomized subjects ( P <0.001). TFPI levels were even higher in the donor quality semen and the PNSP group. TFPI levels also correlated with semen liquefaction time, normal semen viscosity, sperm progression, percentage of motile sperm and sperm counts (density). In conclusion,the present finding substantiates the concept of an active clotting system in human semen. TFPI could regulate the activity of abundant TF, as it does elsewhere. Given a functional set of coagulation factors in semen, the TF/TFPI balance might impinge on its liquefaction and hence on global fertility
Current drug therapy for prostate cancer: an overview
No full textProstate cancer is the most common cancer amongst men in the USA and the second most common malignant cause of male death worldwide after lung cancer. The life time risk of having microscopic evidence of prostate cancer for a 50 year old man in 42%. Prostate cancer is thus becoming an increasingly significant global health problem in terms of mortality, morbidity, as well as economically. This review, discusses current medical therapeutic options for prostate cancer including traditional treatments using luteinising hormone releasing analogues (LHRH), anti-androgens and estrogen treatments, and the use of novel drugs directed against molecular targets considered important in oncogenesis and metastasis. Prostate cancer chemoprevention using 5_-reductase inhibitors and the role of gene therapy are also considered
Cellular resistance to mitomycin C is associated with overexpression of MDR-1 in a urothelial cancer cell line (MGH-U1)
No full textObjective: to compare multidrug resistance (MDR)-1 and MDR-3 gene expression in a new urothelial cancer cell line (MGHU-1, with resistance to mitomycin C) against controls and the established (epirubicin-resistant) MDR clone, and to correlate MDR with cytotoxicity data.Materials and methods: resistance to mitomycin C was induced by the long-term exposure of wild-type MGHU-1 cells to increasing concentrations (20–400 nmol/L) of mitomycin C. The cytotoxicity of mitomycin C or epirubicin was then compared in MGHU-1, MGHU-MMC (mitomycin C-resistant) and MGHU-1R (established MDR) cells, using the tetrazolium biomass assay. The expression of MDR-1 and -3 was investigated by the reverse transcriptase-polymerase chain reaction, using cDNA-specific primers after titration, and compared with DNA and negative controls.Results: MDR-1 and -3 were significantly and equally overexpressed in MGHU-1R, and associated with a dramatic increase in the 50% inhibitory drug concentration (P < 0.001) for mitomycin C and epirubicin against controls. In MGHU-MMC, the overexpression of MDR-1 was three times greater than that of MDR-3. The cytotoxicity profile for both agents was very similar to that of MGHU-1R. Trace amounts of MDR-1, but not MDR-3, were identified in the MGHU-1 wild-type.Conclusions: Urothelial cancer cell resistance to mitomycin C is associated with cross-resistance to epirubicin and overexpression of MDR-1, suggesting that mitomycin C falls within the MDR category. Clinical application of this methodology may allow patients to be identified who are unlikely to benefit from intravesical chemotherapy
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