On the role of additive hormone monotherapy with tamoxifen,medroxyprogesterone acetate and aminoglutethimide,in advanced breast cancer

Summary We analyzed the results of clinical studies on the therapeutic efficacy of hormone monotherapy with tamoxifen, medroxyprogesterone acetate, and aminoglutethimide in metastatic breast cancer, which were published between 1971 and 1986 and involved altogether 7000 patients. The overall response rates in patients treated with these hormonal single agents at various dose levels ranged from 31%–42%. When only estrogen receptor-positive patients were considered, the response rates lay between 41% and 54% in groups which were treated with the antiestrogenic agents tamoxifen or aminoglutethimide. The duration of remission was 12 months for tamoxifen- and aminoglutethimide-treated women, whereas medroxy-progesterone acetate effected remissions lasting from 6–16 months. The overall mean survival from start of therapy in tamoxifen- and aminoglutethimide-treated groups was 20 months, whereas information concerning this therapeutic parameter was available only in a minority of medroxyprogesterone acetate-treated groups. With respect to the response by site of metastatic lesions, all three agents caused a significantly higher degree of remissions in the soft tissue as compared to visceral disease.Abbreviations AG Aminoglutethimide - MPA Medroxyprogesterone acetate - TAM Tamoxifen     

A monoclonal antibody (RH1-38) which inhibits multiple systems of cell-mediated cytotoxicity--II. Evidence that the epitope recognized is involved in a late step in the cytolytic mechanism

A monoclonal antibody (RH1-38) which blocks multiple systems of cell-mediated cytotoxicity was functionally characterized. RH1-38 specifically blocks, in the absence of complement, natural killer (NK) activity (K562 targets) without any effect on NK-K562 conjugate formation. Kinetic studies suggested that the antibody blocks a step that occurs 30-120 min after effector populations are mixed with target cells. Single-cell cytotoxicity assays in agarose, combined with standard 51Cr release assays and Michaelis-Menten analysis revealed that RH1-38 markedly decreases Vmax and the number of active NK cells, again without any effect on the number of target-binding cells. The maximum recycling capacity was usually decreased, but in some experiments unchanged, in the presence of the monoclonal antibody. RH1-38 inhibited equally well whole peripheral blood mononuclear leukocytes (PBML), Percoll-fractionated lymphocytes enriched for NK activity, and interferon (IFN)-boosted NK activity. PBML exposed to RH1-38 and then washed mediated depressed NK activity which was partially reversed by subsequent treatment with IFN. These studies are most consistent with the hypothesis that RH1-38 inhibits a step late in the NK cytolytic mechanism rather than through an effect on conjugate formation. The primary effect is probably not on the IFN-generating or boosting mechanism, but a secondary effect on IFN-related mechanisms cannot be ruled out. Inhibition through an effect on a small lymphocyte modulator of NK activity is also unlikely but not rigorously excluded. Thus, RH1-38 appears to inhibit NK activity through a direct effect on NK effector cells, probably by interfering with a cell-surface molecule which is important in the expression of NK activity. The companion paper demonstrates that this monoclonal antibody immunoprecipitates a molecule which is very similar or identical to the LFA-1 antigen. Thus, RH1-38 recognizes either a novel epitope on the LFA-1 molecule or alternatively a distinct, functional killer cell surface molecule. The epitope appears to be involved in a late step in the cytolytic mechanism, possibly part of the effector cell lytic machinery.     

Polyelectrolyte‐in‐Ionic‐Liquid Electrolytes

Novel polymer electrolyte materials based on a polyelectrolyte‐in‐ionic‐liquid principle are described. A combination of a lithium 2‐acrylamido‐2‐methyl‐1‐propanesulfonic acid (AMPSLi) and N,N′‐dimethylacrylamide (DMMA) are miscible with the ionic liquid, 1‐ethyl‐3‐methylimidazolium dicyanamide (EMIDCA). EMIDCA has remarkably high conductivity (≥ 2 · 10^?2 S · cm^?1) at room temperature and acts as a good solvating medium for the polyelectrolyte. At compositions of AMPSLi less than or equal to 75 mol‐% in the copolymer (P(AMPSLi‐co‐DMAA)), the polyelectrolytes in EMIDCA are homogeneous, flexible elastomeric gel materials at 10 ? 15 wt.‐% of total polyelectrolyte. Conductivities higher than 8 · 10^?3 S · cm^?1 at 30 °C have been achieved. The effects of the monomer composition, polyelectrolyte concentration, temperature and lithium concentration on the ionic conductivity have been studied using thermal and conductivity analysis, and pulsed field gradient nuclear magnetic resonance techniques.

Comparison of the measured and calculated lithium conductivity at 30 °C.     

Ovarian stimulation by clomiphene citrate and hMG in combination with cetrorelix acetate for ICSI cycles

BACKGROUND: The introduction of GnRH antagonists such as cetrorelix acetate has made possible the simplification of ovarian stimulation. However, the most effective protocol for their administration has not yet been clearly defined. METHODS: Forty women with male-factor infertility undergoing 40 ICSI cycles were included in the study. Clomiphene citrate at 100 mg a day was given from cycle day 3 through day 7. hMG at 150 IU was given on cycle days 4, 6 and 8, and was adjusted from day 9 according to the follicular and hormone responses. Cetrorelix acetate at 2.5 mg was administered when the leading follicle reached 14 mm. The remaining 0.5 mg was divided into two 0.25 mg injections for possible later use. Serum FSH, LH, estradiol and progesterone levels were measured daily from the day of cetrorelix acetate injection until hCG was given. RESULTS: Serum LH level was suppressed effectively for 4 days. Four patients (10%) needed one or two additional injections of 0.25 mg cetrorelix acetate. No premature LH surge was detected in any of the women treated. Sixteen women became pregnant (40%), of which 14 pregnancies (35%) were ongoing at the time of writing. CONCLUSIONS: This study demonstrates that this new protocol is feasible for couples with male-factor infertility undergoing ICSI.     

Endocrine toxicology: A Review of the application of endocrinology in experimental toxicology

In the past endocrine toxicology has not been a common subject in routine toxicity studies. However, since the endocrine system is an important integrating system of the body, controlling the major physiological functions, it is important to investigate the mechanism of action of exogenous compounds in endocrine target organs or hormonal target cells. The following procedure is suggested to detect effects on the endocrine system in routine toxicity experiments: (1) determination of the weight of endocrine organs and histology as screening parameters; (2) determination of circulating hormones in combination with morphological or immunocytochemical methods: (3) specific function tests and in vitro methods to determine dysfunction of specific endocrine organs or cells. That the use of such an approach has provided insight into the mechanism of action of chemical compounds will be demonstrated by results of endocrine toxicity studies with the antibiotic compound sulphadimidine, interfering with thyroid hormone synthesis as a secondary mechanism leading to thyroid tumour formation, the androgenic compound trenbolone acetate, used for growth promotion, for which the disturbance of the gonadal function formed the basis for the establishment of the no-observed-hormonal-effect level, the antibacterial compound furazolidone, suspected of having an oestrogenic activity which was hypothesized as the underlying mechanism for the observed mammary tumour formation, and the antimicrobial agent carbadox, used as feed additive for pigs, for which the interference with adrenal function, resulted in a severe disturbance of the water and salt balance in target animals. Originally presented at ECCP 93.     

Decreased tissue inhibitor of metalloproteinase in the endometrium of women using depot medroxyprogesterone acetate: a role for altered endometrial matrix metalloproteinase/tissue inhibitor of metalloproteinase balance in the pathogenesis of abnormal uterine bleeding?

BACKGROUND: Abnormal uterine bleeding is commonly associated with progestin-only contraceptives, including depot medroxyprogesterone acetate (DMPA), and remains the main reason why these agents are discontinued. Matrix metalloproteinases (MMP), enzymes which degrade specific extracellular matrix components, and leukocytes are implicated in menstruation. Alteration in endometrial MMP-9 and leukocytes has been described in users of other progestin-only contraceptives, suggesting a potential role in the pathogenesis of abnormal uterine bleeding. METHODS: This study describes the immunohistochemical localization of MMP-9, the tissue inhibitors of metalloproteinases (TIMP)-1, TIMP-2 and TIMP-3, and leukocytes [CD3+ T lymphocytes, CD68+ macrophages and CD56+ uterine natural killer cells (uNK cells)] in the endometrium of women using DMPA. Comparison is made with perimenstrual endometria from normal cycling women. RESULTS: Similar to the perimenstrual period, an influx of MMP-9 positive cells (identified as neutrophils and CD3+ T cells on the basis of dual immunofluorescence), macrophages and uNK cells was observed in the endometrium of DMPA users. However, significantly more endometrial T lymphocytes were observed in DMPA users. Immunoreactive TIMP, present in all endometrial compartments, demonstrated a significantly decreased immunostaining intensity score in endometrial epithelium (TIMP-1 and TIMP-2), stroma (TIMP-1, TIMP-2 and TIMP-3), endothelium (TIMP-1 and TIMP-2) and vascular smooth muscle (TIMP-1) of DMPA users compared with controls. No correlation was observed between the parameters studied and bleeding patterns reported by subjects. CONCLUSIONS: These findings provide additional evidence for the importance of the MMP/TIMP balance in the loss/maintenance of endometrial integrity and in the complex pathological mechanisms involved in the troubling side-effect of menstrual bleeding disturbance.     

丹参提取物F对大鼠乙醇性胃粘膜损伤的影响及其机制的研究

在大鼠乙醇性胃粘膜损伤模型上，丹参提取物Ｆ ０．１ｍｌ／２００ｇ／ｍｉｎ ｉｖ５分钟可明显降低胃粘膜伊文斯兰含量（Ｐ＜０．０１）和被单星蓝染色的面积（Ｐ＜０．０１）及胃粘膜损伤程度（Ｐ＜０．０１）。用ＴＳ－２００组织光谱分析仪测定大鼠胃粘膜表层血液量和Ｈｂ氧饱和度，表明丹参提取物Ｆ可维持大鼠胃粘膜在６０％乙醇（容积比）后血液量和Ｈｂ氧饱和度基本不变。结果提示：丹参提取物Ｆ有抗大鼠乙醇性胃粘膜损伤作     

白细胞介素2和黄芪多糖对小鼠NK细胞作用的细胞化学和超微结构观察

本文报道在白细胞介素2(IL-2)及黄芪多糖(PA)作用下,小鼠NK细胞的细胞化学和超微结构变化。实验表明,NK细胞酸性磷酸酶、酸性醋酸酯酶及氯醋酸AS-D酯酶均为阳性。经IL-2和PA的处理,前两种酶的活性增加,阳性细胞百分率增高,并与NK活性相关。IL-2培养后的NK细胞超微结构表现为胞体变大,表面不规则,胞质丰富,细胞器增多等特点。     

A randomized controlled trial of goserelin and medroxyprogesterone acetate in the treatment of pelvic congestion

Following identification of the proportion of pelvic congestion among symptomatic patients complaining of chronic pelvic pain, and in a totally asymptomatic group of patients requesting tubal ligation, the efficiency of goserelin acetate versus medroxyprogesterone acetate was compared objectively using pelvic venogram scores, and subjectively by symptom resolution, improvement of psychological status and sexual functioning in a prospective randomized trial in 47 patients with pure pelvic congestion syndrome. Patients received either goserelin acetate (3.6 mg/month for 6 months) or medroxyprogesterone acetate (MPA; 30 mg/day for 6 months). Among patients with chronic pelvic pain, those with pure pelvic congestion were mostly parous, had the most severe pelvic signs and symptom scores, lowest rates of sexual functioning, and higher states of anxiety and depression as compared with others. At 1 year after treatment, goserelin remained superior to MPA in terms of pelvic venographic improvement as an objective measure. In alleviation of signs and symptomatology, improvement of sexual functioning and reduction of anxiety and depressive states as subjective measures, goserelin acetate achieved a statistically significant advantage (P = 0.0001) compared with MPA.