Platelet-derived endothelial cell growth factor was previously identified as the sole angiogenic activity present in platelets; it is now known to be thymidine phosphorylase (TP). Intense interest has recently centered on the angiogenic process, largely as a result of the realization that disregulated blood vessel growth plays a critical role in several disease states, including (inter alia) cancer (tumor angiogenesis), diabetic retinopathy, psoriasis, rheumatoid arthritis, and hyperproliferation of the vasa vasorum in atherosclerosis (1). Platelet-derived endothelial cell growth factor was described as a mitogenic and angiogenic factor present in platelets (2).Platelet-derived endothelial cell growth factor is now known to be thymidine phosphorylase (TP) (3) and the effects of TP on cellular uptake of [methyl-3H]thymidine when it is added exogenously to cells arise from its effect on the availability of thymidine in the extracellular culture medium (4-6). Several years prior to the isolation of the so-called plateletderived endothelial growth factor and demonstration of its angiogenic activity, TP had been identified as an enzyme whose level was significantly elevated in the plasma of cancer patients relative to that in healthy volunteers (7) and in the plasma of xenografted mice relative to that of controls (8) and expressed at a high level in tumors (9, 10). We have found (11) that expression of TP shows a strong correlation with ovarian malignancy and ovarian tumor blood flow.We report here that TP is angiogenic in the rat sponge model (12) and in a freeze-injured skin graft model (13). Expression of TP strongly correlated with malignancy in breast tumors, and while expression of TP had no effect on breast carcinoma cell growth in vitro, it greatly enhanced tumor growth in vivo. MATERIALS AND METHODSCell Isolation and Culture. Bovine aortic endothelial cells were isolated as described (14) and maintained in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% (vol/vol) fetal calf serum. Low-passage MCF-7 cells (passage 53) were a gift from Marc Lippman (Georgetown University, Washington, DC).Antibodies to TP. Rabbit anti-TP antisera and mouse anti-TP monoclonal antibodies were raised against recombinant TP expressed in Escherichia coli (4).Site-Directed Mutagenesis and Protein Expression. Three site-directed mutants of TP were constructed by a two-step PCR (15). Recombinant proteins were expressed in E. coli using the expression vector pET-14b (ams Biotechnology, Witney, U.K.) and purified by metal chelate affinity chromatography. By gel filtration, recombinant TP was dimeric with a molecular mass of 100 kDa. Concentrations of pure TP were calculated by using a molecular mass of 100 kDa.Rat Sponge Angiogenesis Assay. Sterile circular polyether sponge discs with central cannula were implanted subcutaneously in male Wistar rats (180-200 g) after induction of neuroleptanalgesia by Hypnorm (12). Four sponges were used in each experimental group. Protein in 50 ,ul of PBS was injected daily into...

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Traditional Chinese medicine (TCM) is an integral part of mainstream medicine in China. Due to its worldwide use, potential impact on healthcare and opportunities for new drug development, TCM is also of great international interest. Recently, a new era for modernisation of TCM was launched with the successful completion of the Good Practice in Traditional Chinese Medicine Research in the Post-genomic Era (GP-TCM) project, the European Union’s Seventh Framework Programme (FP7) coordination action on TCM research. This 3.5-year project that involved inputs from over 200 scientists resulted in the production of 20 editorials and in-depth reviews on different aspects of TCM that were published in a special issue of Journal of Ethnopharmacology (2012; volume 140, issue 3). In this narrative review, we aim to summarise the findings of the FP7 GP-TCM project and highlight the relevance of TCM to modern medicine within a historical and international context. Advances in TCM research since the 1950s can be characterised into three phases: Phase I (1950s-1970s) was fundamental for developing TCM higher education, research and hospital networks in China; Phase II (1980s-2000s) was critical for developing legal, economic and scientific foundations and international networks for TCM; and Phase III (2011 onwards) is concentrating on consolidating the scientific basis and clinical practice of TCM through interdisciplinary, interregional and intersectoral collaborations. Taking into account the quality and safety requirements newly imposed by a globalised market, we especially highlight the scientific evidence behind TCM, update the most important milestones and pitfalls, and propose integrity, integration and innovation as key principles for further modernisation of TCM. These principles will serve as foundations for further research and development of TCM, and for its future integration into tomorrow’s medicine.

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In this study, women with dysmenorrhea of at least 6 months' duration were recruited to a randomized, double-blind, controlled trial, which compared the effectiveness of conservative surgical treatment with treatment with presacral neurectomy. One hundred twenty-six women with a diagnosis of dysmenorrhea caused by endometriosis who had been unresponsive to medical treatment formed the study subjects. A preoperative evaluation established a baseline for frequency and severity of dysmenorrhea, dyspareunia, and chronic pelvic pain. Similar measurements were made at 6 and 12 months. Pain severity was rated using a 100-point visual analog scale with 100 being the most severe pain. Patients were randomized to 1 of 2 treatment groups. Group A (n ϭ 63) received electrocautery ablation or excision of visible pelvic endometriotic lesions, enucleation of endometriomas, and lysis of pelvic adhesions. Group B (n ϭ 63) underwent presacral neurectomy after conservative treatment. Presacral neurectomy was performed after retraction of the sigmoid colon and vasopressin infiltration of the sacral promontory area. The presacral area was exposed and underlying tissue layers cauterized. At the periosteum, a semilunar piece of retroperitoneal tissue was dissected. Neurectomy was confirmed with pathologic examination of this tissue for evidence of nerve fiber presence. The 2 treatment groups were similar in demographic and clinical data. All laparoscopies were successfully completed with no surgical complications in either group. The length of surgery was significantly greater for those in group B (mean 123 minutes vs. 110 minutes; P Յ.05), but otherwise all operative parameters were similar. Short-term complications were minimal in both groups. No patient in group A had long-term complications. In group B, 21 and 9 women, at the 6-and 12-month visits, respectively, reported constipation. Medical therapy was successful in 15 of the 21 women at 6 months. Three patients reported urinary urgency at both the 6-and 12-month follow up. At the 6-month and 12-month visits, 83.2% and 85.6%, respectively, of the patients in group B reported either no dysmenorrhea or only light discomfort and were considered cured. In comparison, 60.3% and 57% of the women in group A were cured at 6 and 12 months, respectively (P Յ.05 for both). At each stage of endometriosis, and in women with deep rectovaginal septum endometriosis, the cure rate in group B was significantly higher compared with those in group A. Women in group A who had deep rectovaginal septum endometriosis were less likely to be cured compared with all stages of endometriosis in the same group. The severity of dysmenorrhea and dyspareunia was significantly improved at the 6-and 12-month visit in group B compared with group A, but the frequency of symptoms was similar in both groups after treatment. ABSTRACTTwo hundred nulliparous women were enrolled in a prospective observational study to investigate the influence of childbirth on pelvic organ mobility. The mobility of the urethra, bladder, c...

1 Daily administration of 1 nmol substance P or 3 pmol recombinant human interleukin-1 alpha (IL-la) caused intense neovascularization in a rat sponge model of angiogenesis. Lower doses of substance P (10 pmol) or IL-lh (0.3 pmol) were ineffective when given alone. When combined at these low doses, substance P and IL-lo interacted to produce an enhanced neovascular response.2 By use of selective tachykinin NK,, NK2 and NK3 receptor agonists, ([Sar9,Met(02)' ]substance P, [P-Ala8]neurokinin A(4-10), Succ-[Asp6,MePhe8]substance P(6-11) (senktide), respectively), it was established that the activation of NK, receptors is most likely to mediate the angiogenic response to substance P in this model.3 The angiogenic activity of substance P and IL-lh (10 pmol and 0.3 pmol day-', respectively) was abolished by co-administration of (i) the selective peptide NK, receptor antagonist, L-668, 169 (1 nmol day-'), (ii) the selective non-peptide NK, receptor antagonists, RP 67580 and (±)-CP-96,345 (both at 1 nmol day-') or (iii) the IL-1 receptor antagonist, IL-Ira, (50 g day-'). In contrast, the selective NK2 receptor antagonist, L-659,874 (1 nmol day-') was ineffective. 4 The angiogenic action of substance P and IL-lh was resistant to modification by mepyramine (1 nmol day-') and/or cimetidine (10 nmol day-'), indomethacin (7 nmol day-') or the plateletactivating factor (PAF) antagonist, WEB-2086 (22 nmol day-'), indicating that histamine, prostaglandins and PAF are not likely to be involved in this neovascular response.5 The inhibition of the substance P/IL-I angiogenic response by selective NK, receptor antagonists or by an IL-1 receptor antagonist demonstrates that angiosuppression can be achieved by blocking the activity of angiogenic factors at the receptor level.

Endometriosis is a disease in which the lining of the uterus (endometrium), shed at the time of menstruation, becomes established at sites such as the peritoneum and ovaries. These explants develop a rich blood supply that enables them to survive and grow. We hypothesized that inhibitors of angiogenesis would prevent this growth by disrupting sensitive vessels supplying endometriotic lesions. Vessels sensitive to angiogenic antagonism have few associations with pericyte cells. The vessels supplying human endometriotic lesions were immunohistochemically characterized and found to be predominantly pericyte free. A model in which human endometrium is implanted into nude mice was used to test the effects of two antagonists of the angiogenic growth factor, vascular endothelial cell growth factor A. Soluble truncated receptor (flt-1; P = 0.002) and an affinity-purified antibody to human vascular endothelial cell growth factor A (P = 0.03) significantly inhibited the growth of nude mouse explants. Pericyte-free vessels were shown to supply endometrial lesions in nude mice and were disrupted in lesions taken from soluble flt-1-treated mice. In summary, antiangiogenic agents inhibited the growth of explants in an in vivo model of endometriosis by disrupting the vascular supply, and this effect is likely to apply to the human disease. These findings suggest that antiangiogenic agents may provide a novel therapeutic approach for the treatment of endometriosis.

Research on herbal medicinal products is increasingly published in “Western” scientific journals dedicated primarily to conventional medicines. Publications are concerned mainly not only on the issues of safety and interactions, but also on efficacy. In reviews, a recurring complaint has been a lack of quality studies. In this opinion article, we present the case of Chinese herbal medicines as an example, as they have been extensively used in the global market and increasingly studied worldwide. We analyze the potential reasons for problems and propose some ways forward. As in the case of any drug, clinical trials for safety, efficacy, and/or effectiveness are the ultimate demonstration of therapeutic usefulness of herbal products. These will only make scientific sense when the tested herbal products are authentic, standardized, and quality controlled, if good practice guidelines of evidence-based medicine are followed, and if relevant controls and outcome measures are scientifically defined. Herbal products are complex mixtures, and for such complexity, an obvious approach for mechanistic studies is network pharmacology based on omic tools and approaches, which has already begun to revolutionize the study of conventional drugs, emphasizing networks, interactions, and polypharmacological features behind the action of many drugs.