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Biomedical subjects

M A Blankenstein

Publications and source records attributed to M A Blankenstein.

At least 19 recordsLinked to original sources
PubMed2007

C21ORF105, A chromosome 21-encoded mRNA, is not a discriminative marker gene for prediction of Down syndrome in maternal plasma.

OBJECTIVES: The presence and detectability of placental mRNA in maternal plasma opens possibilities for the development of non-invasive prenatal diagnostic tests. In this study, we tested C21orf105, a chromosome 21-encoded, placentally expressed gene, in maternal plasma of women carrying a fetus with or without trisomy 21. METHODS: Using real-time RT-PCR, we determined transcript levels of target (C21orf105) and reference (hPL) genes in first-trimester plasma samples. Plasma was obtained from first-trimester EDTA blood after two sequential centrifugation steps and stored at -70 degrees C. After RNA extraction, quantitative RT-PCR was performed using Taqman probes. RESULTS: From the 51 samples, 43 samples were conclusive. Comparison of transcript levels of C21orf105 in both groups showed no significant differences. When expressed as ratios of hPL/C21orf105, the differences between trisomy 21 and normal pregnancies remained non-significant. CONCLUSIONS: The amount of C21orf105 mRNA in maternal plasma, although situated in the Down syndrome critical region on chromosome 21 and up regulated in trisomy 21 placentas, is not higher in women carrying a fetus with trisomy 21.

Adult↗
PubMed2006

CSF biomarkers and medial temporal lobe atrophy predict dementia in mild cognitive impairment.

OBJECTIVE: To study CSF biomarkers, beta-amyloid(1-42) (Abeta(1-42)) and tau, and medial temporal lobe atrophy (MTA) on MRI in their ability to predict dementia in patients with mild cognitive impairment (MCI). METHODS: Fifty-nine MCI patients (49% male, mean age 69+/-8), follow-up 19 months, were included. Baseline CSF levels of Abeta(1-42), tau and MTA-score were dichotomized. RESULTS: Thirty-three (56%) of the MCI patients progressed to dementia, 30 of which had Alzheimer's disease. Lower CSF Abeta(1-42) level, higher CSF-tau and higher MTA-scores at baseline were found in progressed patients. Cox proportional hazards models revealed that abnormal CSF Abeta(1-42), CSF tau and MTA were significantly associated with dementia at follow-up (hazard ratio (95% confidence interval): 4.0 (1.3-12.1), 5.9 (1.6-21.7) and 2.1 (1.0-4.6)). A fourfold higher risk was found for patients with both abnormal CSF biomarkers and MTA compared to patients with either test abnormal. Ninety-four percent of patients with both abnormalities converted to dementia. CONCLUSIONS: These findings suggest an added value of CSF to MRI in the diagnostic work up of patients presenting at a memory clinic.

Aged↗
PubMed2006

Urinary gonadotropin measurements in neonates: a valuable non-invasive method.

BACKGROUND: To measure low neonatal gonadotropin levels, a sensitive non-invasive method is optimal. The aim of the current study was to validate the Architect i2000SR, an automated immunoassay analyser for the measurement of gonadotropins in unextracted neonatal urine samples against serum gonadotropin levels as a gold standard. METHODS: Blood and urine were sampled from 30 approximately six-week-old male and female neonates undergoing elective paediatric surgery. Follicle stimulating hormone (FSH) and luteinizing hormone (LH) were measured and the urine results were corrected for creatinine. RESULTS: The agreement between neonatal serum and urinary FSH was 0.904 (3-5 h between samples) and 0.704 (18-20 h). For LH, the correlation coefficients were 0.785 and 0.507, respectively. CONCLUSION: We conclude that gonadotropins can be reliably measured using the Architect on randomly voided, non-extracted urine samples collected from neonates by an adhesive device. Urinary gonadotropin levels are a proper reflection of the serum levels.

Adult↗
PubMed2005

Vitamin D status among patients with hip fracture and elderly control subjects in Yekaterinburg, Russia.

PURPOSE: Vitamin D deficiency leads to secondary hyperparathyroidism and osteomalacia, and both conditions are associated with fractures, the most severe being hip fracture. The serum 25-hydroxyvitamin D level depends on latitude and season. Yekaterinburg is situated at a high latitude and the duration of winter is about 5 months. METHODS: In this study, the serum 25(OH)D and PTH concentrations, and the prevalence of hypovitaminosis D in elderly people, inhabitants of Yekaterinburg, were investigated. The study was performed on 63 people with hip fracture (mean age, 68.8 years) and 97 independently living elderly people (mean age, 70.2 years). RESULTS: Serum 25(OH)D (mean+/-SD) in the hip fracture group was 22.4+/-11.4 nmol/L, significantly lower than in control group, which was 28.1+/-10.1 nmol/L. The percentage of patients with severe hypovitaminosis D (<25 nmol/L) in the hip fracture group was 65%, compared to 47% in the control group (p<0.05). The prevalence of hypovitaminosis D among hip fracture patients, as well as among independently living elderly people in Yekaterinburg, was high. CONCLUSION: Supplementation of vitamin D in elderly people with and without fracture might prevent secondary hyperparathyroidism, osteomalacia and fractures.

Aged↗
PubMed2005

Prognostic value of mitotic counts in axillary node negative breast cancer patients with predominantly well-differentiated tumours.

AIMS: In axillary node negative (ANN) breast cancer patients additional prognostic markers are needed to decide whether adjuvant systemic treatment might be useful. METHODS: In the present study, the prognostic relevance of mitotic counts and Bloom-Richardson grade (BR-grade) was evaluated in 164 ANN breast cancer patients. No adjuvant systemic treatment was given to any of these patients. Mitotic counts were determined twice, in routine practice and in revision. RESULTS: A substantial reproducibility of mitotic counts was found, provided that the cut-off value chosen was high enough. After a median follow-up of 10 years, mitotic counts had no prognostic significance for survival at any cut-off value. A trend towards a significant worse survival was found for patients with Bloom-Richardson grade II or III in comparison with grade I. CONCLUSIONS: Based on data in the literature a positive association between both mitotic counts and BR-grade and survival in ANN breast cancer may exist, but the extent of this putative association and its clinical relevance can be argued, particularly in a group of patients with predominantly well differentiated tumours.

Aged↗
PubMed2003

Elevated C-reactive protein levels during first trimester of pregnancy are indicative of preeclampsia and intrauterine growth restriction.

C-reactive protein (CRP) is a marker of tissue damage and inflammation. Maternal levels of CRP are elevated in overt preeclampsia, but there is still debate about its use as a predictive marker for preeclampsia during the first and second trimesters of pregnancy. In this study, we measured CRP levels during the first trimester of pregnancy in women who later developed preeclampsia or gave birth to a growth-restricted baby. In total, 107 women from a low-risk population participated in the study, six women developed preeclampsia and nine gave birth to a growth-restricted baby. Although there is a large overlap in measured CRP levels between the three groups, mean CRP levels were significantly elevated in women who later developed preeclampsia (P=0.031) or delivered a growth-restricted baby (P=0.041) when compared with women from the control group, matched for maternal and gestational age, parity, and gravidity. This study shows that in a low-risk population, CRP levels are already elevated between weeks 10 and 14 in pregnant women who develop preeclampsia or deliver a growth-restricted baby.

Birth Weight↗
PubMed2003

Do cycle disturbances explain the age-related decline of female fertility? Cycle characteristics of women aged over 40 years compared with a reference population of young women.

BACKGROUND: The cause of declining fertility with age, in women who still have regular menstrual cycles, is not clear. METHODS: Follicle development, endometrial growth and hormonal patterns were evaluated in cycles of older women (aged 41-46 years; n = 26) who previously were normally fertile, and these cycles were compared with a reference group of relatively young fertile women (aged 22-34 years; n = 35). RESULTS: Clearly abnormal cycles were found in only two women in the older age group, and in one woman in the younger group. The main differences between the age groups were a shorter follicular phase and cycle length in the older group, in combination with higher FSH levels in the late luteal and early follicular phase. In contrast to published data which suggest an "accelerated" follicle development in older women, sonographical and hormonal evidence was found of an "advanced" follicle growth, with an earlier start already during the luteal phase of the preceding cycle, and an advanced selection and ovulation of the dominant follicle. CONCLUSIONS: Such an earlier start of follicle growth in a possibly less favourable hormonal environment, as well as a limited oocyte pool, may contribute to a decreased follicle and oocyte quality, resulting in diminished fertility in ageing women.

Adult↗
PubMed2002

Effect of tibolone (Org OD14) and its metabolites on aromatase and estrone sulfatase activity in human breast adipose stromal cells and in MCF-7 and T47D breast cancer cells.

Tibolone (Org OD14) is a synthetic steroid used for post-menopausal hormone replacement therapy (HRT). Since HRT might increase breast cancer risk, it is important to determine the possible effects of tibolone on breast tissues. Tibolone and its metabolites Org 4094, Org 30126 and Org OM38 have been reported to inhibit estrone sulfatase activity in MCF-7 and T47D breast cancer cell lines, which suggest beneficial effects on hormone dependent breast cancer by reducing local production of free estrogens. Breast adipose stromal cells (ASCs) contain aromatase activity-an obligatory step in the biosynthesis of estrogens-and possibly contain sulfatase activity. We investigated the effects of tibolone, its metabolites and the pure progestin Org 2058 on PGE(2)-stimulated aromatase activity and on sulfatase activity in human ASC primary cultures and on sulfatase activity in MCF-7 and T47D cell lines. In MCF-7, tibolone and metabolites, but not Org 2058, were found to inhibit sulfatase activity. In T47D, tibolone inhibited sulfatase only at 10(-6)M, although weakly. ASC had high sulfatase activity, which was inhibited by 10(-6)M of tibolone, Org 4094 and Org 30126, but not by Org OM38 or Org 2058. Surprisingly, aromatase activity in ASC was increased by both tibolone and Org 2058 at 10(-6)M. As ligand binding assay results and immunohistochemistry indicated the absence of progesterone and estrogen receptors in ASC, these effects on aromatase and sulfatase activity in ASC likely take place by other routes. Because tibolone and its metabolites inhibit sulfatase activity, and because tibolone only increases aromatase activity at a high concentration, we conclude that effects of tibolone on the breast are probably safe.

17-Hydroxysteroid Dehydrogenases↗
PubMed2002

Progesterone receptor, bc1-2 and bax expression in meningiomas.

Meningiomas are generally benign central nervous system neoplasms, which frequently express progesterone receptor (PR) and only rarely express the estrogen receptor (ER). For breast cancer, a relation between steroid hormone receptors and proteins involved in the apoptotic process has been described. For meningiomas, the exact relation between PR and these proteins is not known. In this study, ER, PR, bcl-2 and bcl-2-associated x protein (Bax) expression levels were determined in meningioma cytosols. As a reference for our experimental conditions, we also determined these proteins in breast cancer cytosols. PR and ER were determined with a ligand-binding assay and scatchard-plot analysis. The expression levels of the anti- and pro-apoptotic proteins, bcl-2 and Bax, respectively, were determined by immunoblotting. In 65% of the meningioma, bcl-2 expression was found in variable amounts. In contrast to breast cancer, a significant negative association between PR and bcl-2 was found (P < 0.01). Bax expression appeared constitutive, not related to PR, and 2.6 times higher than breast cancer. As both PR and bcl-2 appear positively associated with prognosis, the negative relationship between bcl-2 and PR found in this study might have some biological and clinical significance.

Apoptosis↗
PubMed2002

Progesterone receptors in normal, dysplastic and tumourous feline mammary glands. Comparison with oestrogen receptors status.

The aims of the study were to standardise an immunohistochemical (IHC) method for the detection of progesterone receptors (PR) on formalin-fixed, paraffin wax-embedded tissue sections of feline mammary gland tumours and dysplasias, comparing the results with those obtained using the radiolabelled ligand dextran coated charcoal (DCC) assay applied to frozen tissue samples from the same cases. Also, to define the immunohistochemical distribution of PR in the different cellular compartments of the lesions and to compare the oestrogen receptor (ER) and PR status of the feline mammary lesions. Proliferative mammary lesions collected from 34 cats were studied; 25 malignant tumours and 9 benign tumours and dysplasias. PR protein was present at a concentration of 5 fmol mg(-1) (positivity threshold) in 37.5 per cent of malignant tumours and 66.7 per cent of benign tumours and dysplasias while immunoreative products to PR antibody were found in the nuclei of tumour cells in 38.5 per cent and 66.7 per cent of the cases, respectively. Concordance between DCC-PR and IHC-PR was 88.5 per cent (P<0.001). The specificity (true negatives) and sensitivity (true positives) of the IHC method were 89.4 per cent and 87.5 per cent respectively. The presence of PR was linked to the absence of ovariectomy (P<0.02). Oestrogen receptors, detected by either method, were also detected in half the cases in which PR had been detected. In malignant tumours, the most prevalent groups were the ER + PR + and ER-PR + groups.

Adenocarcinoma↗
PubMed2001

Progesterone receptor isoform expression in human meningiomas.

The majority of meningiomas express the progesterone receptor (PR), and therefore meningiomas are considered to be progesterone-responsive. In addition, an association has been reported between PR and prognosis. At least two PR isoforms exist, PR-B (116--120 kDa) and PR-A (81 kDa), each of which are likely to have different biological functions. Knowledge of the differential expression of both isoforms is necessary to understand the effects of progesterone on meningioma growth. Therefore, in this study, PR-A and PR-B expression levels were determined in 61 human meningiomas by immunoblotting. Total PR expression levels were determined with a ligand binding assay (LBA) (total PR(LBA)). Both PR isoforms and an additional PR 78 kDa protein (PR-78) were expressed in the meningiomas. Meningiomas expressing more PR-A than PR-B had significantly higher total PR(LBA) levels (P<0.001). The PR-78 band intensity was negatively associated with that of PR-B (r(s)=-0.76, P<0.0001). PR-78 may represent an endogenous degradation product, but a similar regulation pathway in the biogenesis of both PR-B and PR-78 is not excluded. Meningiomas contain both PR isoforms, but in highly variable ratios and this variability may have some biological significance. Most meningiomas express more PR-A than PR-B. Therefore in meningioma, assuming that PR-B is more transcriptionally active than PR-A, progesterone responsiveness could be based on transrepression rather than on transactivation of target genes, and progesterone blockade may only be effective in certain subsets of meningiomas.

Aged↗
PubMed2001

Aromatase and COX-2 expression in human breast cancers.

We have investigated aromatase and the inducible cyclooxygenase COX-2 expression using immunocytochemistry in tumors of a series of patients with advanced breast cancer treated with aromatase inhibitors. Aromatase was expressed in 58/102 breast cancers. This is similar to the percentage previously reported for aromatase activity. Interestingly, aromatase was expressed in a variety of cell types, including tumor, stromal, adipose, and endothelial cells. Since prostaglandin E2 is known to regulate aromatase gene expression and is the product of COX-2, an enzyme frequently overexpressed in tumors, immunocytochemistry was performed on the tissue sections using a polyclonal antibody to COX-2. Aromatase was strongly correlated (P<0.001) with COX-2 expression. These results suggest that PGE2 produced by COX-2 in the tumor may be important in stimulating estrogen synthesis in the tumor and surrounding tissue. No correlation was observed between aromatase or COX-2 expression and the response of the patients to aromatase inhibitor treatment. However, only 13 patients responded. Nine of these patients were aromatase positive. Although similar to responses in other studies, this low response rate to second line treatment suggests that tumors of most patients were no longer sensitive to the effects of estrogen. Recent clinical studies suggest that greater responses occur when aromatase inhibitors are used as first line treatment. In the intratumoral aromatase mouse model, expression of aromatase in tumors is highly correlated with increased tumor growth. First line treatment with letrozole was effective in all animals treated and was more effective than tamoxifen in suppressing tumor growth. Letrozole was also effective in tumors failing to respond to tamoxifen, consistent with clinical findings. In addition, the duration of response was significantly longer with the aromatase inhibitor than with tamoxifen, suggesting that aromatase inhibitors may offer better control of tumor growth than this antiestrogen.

Adipocytes↗
PubMed2001

Importance of local aromatase activity in hormone-dependent breast cancer: a review.

The cytochrome P-450 enzyme complex aromatase is the rate-limiting step in the production of oestrogens. It catalyses the conversion of androgens to oestrogens. In the treatment of hormone-dependent breast cancer in postmenopausal women, aromatase is the target for treatment with aromatase inhibitors. Recently registered aromatase inhibitors like anastrozole, letrozole and exemestane have proven to be effective therapy for advanced breast cancer in postmenopausal patients failing to respond to treatment with tamoxifen. Intratumoural aromatase activity has predictive value for response to treatment with aromatase inhibitors. Attempts are being made to find an immunohistochemical technique to determine aromatase in tumour tissue, which may serve as a predictive factor. In situ oestrogen synthesis through local aromatase activity in the tumour and adjacent tissue is probably a very important growth-stimulating system in hormone-dependent breast cancer. This synthesis can be blocked with aromatase inhibitors. The regulation of aromatase activity and the cell types that contribute to this process are the subject of extensive research. There seems to be a complex interaction between malignant cells and adjacent cells in which factors such as IL-6 and its soluble receptor, TNF-alpha and prostaglandin E2 play an important role in stimulating aromatase activity.

Journal Article↗
PubMed2001

Levels of estrogen and progesterone receptors in the myometrium and leiomyoma tissue after suppression of estrogens with gonadotropin releasing hormone analogs.

Gonadotropin releasing hormone (GnRH) agonists are successfully used in the treatment of uterine leiomyomas. Different GnRH agonists may have different local effects on steroid receptors. This study was designed to evaluate potential differences in this respect between triptorelin (Decapeptyl) and goserelin (Zoladex) in a randomized controlled multicenter study using untreated patients during the luteal phase of their menstrual cycle as controls. Estrogen receptors (ERs) and progestin receptors (PRs) were measured by ligand binding assay in myoma and myometrium tissue following a 4-month treatment course with one of the GnRH analogs. In 18 untreated patients median values of ER and PR contents were comparable in myoma and myometrium: for ER at median levels of 56 and 43 fmol/mg protein, respectively; and for PR, median binding capacities were 690 and 730 fmol/mg protein, respectively. Both types of GnRH treatment (total number of patients 34) were associated with significant rises in ER in myoma (to a median level of 279 fmol/mg protein, p<0.001) and myometrium (to a median level of 109 fmol/mg protein, p<0.01). The increase in ER in myomas was significantly (p<0.001) greater than in myometria of the same patients (n=30). After treatment, PR in myomas (median level 520 fmol/mg protein) did not change significantly, but a significant (p<0.05) decrease was found for myometria (median level of 320 fmol/mg protein). Thus, ER and PR concentrations in myoma and myometrium are comparable before treatment, but estrogen suppression with GnRH analogs leads to a larger increase of ER level in leiomyomas than in myometrium, without an effect on PR, whereas myometria had lower PR levels. Therefore, leiomyoma reacts differently from myometrium towards lowered steroid concentrations in the circulation. Since the PR is considered to be a marker of estrogenic stimulation, this indicates remaining estrogenic effects on leiomyomas despite the large decrease of plasma estrogen concentrations.

Estradiol↗
PubMed2000

Basal follicle-stimulating hormone levels are of limited value in predicting ongoing pregnancy rates after in vitro fertilization.

OBJECTIVE: To evaluate whether basal FSH (bFSH; measured on menstrual day 1-4) adds relevant clinical information to the prediction of ongoing pregnancy rates (OPRs) after IVF, once age and diagnostic characteristics have been taken into account. DESIGN: Retrospective. SETTING: Academic fertility center. PATIENT(S): 435 women undergoing their first IVF cycle. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Ongoing pregnancy rate. RESULT(S): The likelihood ratio of bFSH as a single prognosticator for treatment failure at a cutoff level of 15 IU/L was 3.87. The proportion of patients with such a bFSH level was 5%. Multivariate logistic regression analysis selected age, bFSH level, and infertility diagnosis as relevant predictors of ongoing pregnancy. When compared to a predictive model for OPRs based on age and infertility diagnosis, the inclusion of bFSH into this model helped to identify more patients (22 vs. 1) whose predicted OPR decreased from a low level (5%-12%) towards an extremely low level (<5%). CONCLUSION(S): An acceptable performance of bFSH as a single test to predict treatment failure is only obtained above a high cutoff level. Thus, the number of patients for whom bFSH provides relevant information is small. The predictive model including bFSH identified significantly more patients with an extremely poor prognosis than did the predictive model without bFSH. However, predictions based solely on age and infertility diagnosis usually were already poor in these patients. Measurement of bFSH adds little in only a few patients and is, therefore, debatable.

Adult↗