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.     

Bradyphrenia in parkinsonism: a historical review

The development over the last 60 years of the concept of bradyphrenia, a syndrome including slowing of cognitive processing in parkinsonism, is described. Psychic akinesia and subcortical dementia are seen as more recent synonyms for this syndrome. Its relations to akinesia and the psychomotor retardation of depression are considered in a historical context, as are its implications for the relation of neurological and psychiatric disorder.     

Influence of different hormonal regimens on endometrial microvascular density and VEGF expression in women suffering from breakthrough bleeding

BACKGROUND: The aim of this study was to quantify blood vessel density (BVD) and immunoreactive vascular endothelial growth factor (VEGF) levels in endometrial biopsies taken from women suffering breakthrough bleeding (BTB) under different exogenous hormonal regimes. METHODS: Endometrial biopsies from women in Melbourne with BTB were divided into four groups: combined-continuous hormone therapy (HT) (estrogen and progestin taken daily), cyclical HT (daily estrogen with progestin for 14 days each cycle), progestin-only, or no HT. Subjects from Barcelona were using the Mirena intrauterine levonorgestrel-releasing system for contraceptive purposes, with menstrual diaries for classification into four groups (amenorrhea, infrequent, regular and prolonged). Control biopsies from Melbourne were included in the study. Endometrial samples were immunostained for VEGF and blood vessel localization using an antibody to CD34. RESULTS: Results showed that BVD was significantly reduced in the progestin-only treated group compared with the other three treatment groups (P = 0.028). In addition, all four Mirena BTB groups had significantly reduced BVD compared with controls. Considerable heterogeneity was observed in VEGF immunostaining within and between individual samples with no major differences between HT or Mirena. CONCLUSION: These results provide strong evidence that unopposed progestins reduce endometrial BVD and that there is no link between VEGF immunostaining and BVD or BTB.     

Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer's disease

HLA-DR is a class II major histocompatibility complex antigen which in the periphery confers antigen presenting capability. We have previously shown that this marker is profusely expressed in cortex of elderly and Alzheimer's disease (AD) patients, as is the receptor for the lymphokine interleukin-2. We now report presence of additional immune-related antigens in AD, and distributional differences from normal elderly controls. In gray matter, HLA-DR immunoreactivity is normally sparse, except in AD where it co-localizes with virtually all neuritic plaques. HLA-DR positive T cells can be demonstrated in Alzheimer's disease brain tissue, as can instances of apposition between putative brain microglia and T cells. In addition, cells with the morphologic characteristics of astrocytes label for natural killer cell antigen (Leu-11), and apparent lymphocytes bearing T helper and T cytotoxic/suppressor cell antigens are observed. These and other data suggest that the glial proliferation and scavenger activity characteristic of Alzheimer's disease may occur in an immune context and may play an important role in the pathogenesis of the disorder.     

Changing activities of galactose-metabolizing enzymes during perfusion of suckling-rat liver

The specific activities of the galactose-metabolizing enzymes, galactokinase (EC 2.7.1.6), galactose-1-phosphate uridyltransferase (EC 2.7.7.12), and UDPgalactose 4-epimerase (EC 5.1.3.2), in suckling-rat livers perfused for 90 min with 1 and 4 mM galactose fluctuate significantly with a different pattern of change for each enzyme. Perfusion for 30 min with galactose resulted in a significant increase of transferase specific activity followed by a precipitous decline to about one-fifth of the activity in unperfused liver at 90 min. The increase in transferase activity was also observed when D-glucose was perfused but not when L-glucose, D-fructose, D-xylose, or D-ribose was added to the perfusate. No such changes in transferase activity were observed when adult-rat liver was perfused with galactose. Epimerase activity in the suckling-rat liver was relatively low, and the changes in its activity correlated best with the uptake rate of galactose. The perfused suckling-rat liver may provide a model system for examination of factors that modulate the specific activity of galactose-metabolizing enzymes and effect the metabolism of galactose.     

Recurrent wavefront morphologies: A method for quantifying the complexity of epicardial activation patterns

We have developed a method for quantifying the complexity of activation patterns observed during ventricular fibrillation (VF) that is based on our previously reported methodology for decomposing epicardial mapping data into a set of isolated wavefronts. One-half second datasets are acquired from a 21×24 array of unipolar electrodes (1 mm spacing), and the wavefronts are isolated. A correlation technique is used to compute the similarity between all possible pairs of the isolated wavefronts. From these data, the wavefronts are sorted into clusters, each of which represents a recurring wavefront morphology. We define multiplicity (M) as the number of clusters needed to account for 90% of the total activations in the VF episode.M measures the complexity of the rhythm. In repetitive patterns (e.g., sinus rhythm),M=1, indicating that the same morphology repeatedly activates the mapped region. Typically, in VF,M>1, with larger numbers representing more complex, disorganized patterns. As an example, we computedM at 5, 10, 15, and 20 sec after electrical induction of VF in six pigs.M decreased significantly (p<0.001), suggesting increasing organization during this period.     

Glycoproteins present in human follicular fluid that inhibit the zona- binding capacity of spermatozoa

Previous studies have suggested that human follicular fluid contains factors that reduce the zona-binding capacity of spermatozoa. The present study provides further evidence of the existence of such factors. Using the hemizona binding assay (HZA), we have shown that the inhibitory effect of human follicular fluid on the zona-binding capacity of spermatozoa is concentration-dependent, an inhibitory effect being detected when the concentration of human follicular fluid was > or = 10%. A 1% concentration of human follicular fluid did not possess this inhibitory activity. Heating human follicular fluid at 56 degrees C for 30 min did not affect its inhibitory properties; treatment with proteinase-K abolished such inhibition. Human follicular fluid was fractionated sequentially by concanavalin-A affinity chromatography, Mono Q ion-exchange chromatography and Superose-12 gel filtration. The zona binding inhibitory activity resided in the fraction which bound to the lectin and Mono Q column and contained molecules with native molecular weights of 32 and 192 kDa. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis analysis suggested that the 192 kDa glycoprotein was a tetramer, while the 32 kDa glycoprotein remained as a single molecular species under denaturing conditions. We conclude that two glycoproteins were responsible for the zona binding inhibitory activity of human follicular fluid. The physiological role of these factors remains unclear.      

Immunohistology of oestrogen receptor and D5 antigen in breast cancer: correlation with oestrogen receptor content of adjacent cryostat sections assayed by radioligand binding and enzyme immunoassay.

Two monoclonal antibodies recognising epitopes associated with oestrogen receptor protein were evaluated against the assayable soluble oestrogen receptor concentration in a series of 149 breast carcinomas. One antibody (anti-ER) recognises the hormone binding unit of oestrogen receptor and gives nuclear staining; the other antibody (anti-D5) was raised to a component of soluble oestrogen receptor and gives cytoplasmic staining. To minimise variations attributable to tumour heterogeneity and sampling error immunohistology using the two monoclonal antibodies, radioligand binding assays, enzyme immunoassays, and quantitative histology were done on adjacent frozen sections. Thirty nine per cent, 48%, 54%, and 43% of the tumours were found to be oestrogen receptor positive by radioligand binding assay, anti-ER and anti-D5 immunohistology, and enzyme immunoassay, respectively. Strong correlations (p less than 0.0005) were found between anti-ER immunohistology and the radioligand binding assay. Only weak correlations were found between anti-D5 immunohistology and the results of other assay methods for oestrogen receptor. Nuclear staining of human breast cancers with the anti-ER monoclonal antibody thus seems to be an acceptable alternative to biochemical assays, with the additional advantage of showing intercellular and regional heterogeneity for oestrogen receptor content.