Ethnic Differences in Loneliness, Depression, and Malnutrition Among Older Adults During COVID-19 Quarantine.

BACKGROUND: Depression in older adults may result from a variety of reasons such as loneliness feelings and malnutrition. OBJECTIVE: To examine the direct and indirect effect of loneliness feelings on depressive symptoms, mediated by malnutrition, among older adults from different cultures during the Coronavirus disease 2019 (Covid-19) pandemic quarantine. METHOD: A convenience sample of 101 Arabs and 100 Jewish older adults aged 65 and over was interviewed. Using bootstrapping, we tested the strength and significance of the conditional indirect effect of malnutrition (mediator) on the relationship between loneliness feelings and depressive symptoms. RESULTS: The relationship between loneliness feelings and depressive symptoms was mediated by malnutrition and Arab older adults reported a higher level than Jewish older adults of loneliness, depression, and malnutrition during the Covid-19 pandemic quarantine. CONCLUSIONS AND IMPLICATIONS: To reduce loneliness feelings, depressive symptoms, and malnutrition in times of crisis like the Covid-19 pandemic, it is essential to develop new communication methods for and with older adults in general, with particular attention paid to ethnic differences, that will be effective in reducing loneliness and in promoting nutrition intervention. Possible solutions include new social network technologies for reducing loneliness, with continued reliance on phone communication for combined intervention that includes psychological support accompanied by instructions for a healthy lifestyle and malnutrition prevention.

Imaging-based prostate cancer screening among BRCA mutation carriers-results from the first round of screening.

BACKGROUND: Male-carriers of BRCA1/2 gene mutations have an increased risk of prostate cancer (PCa) with a more aggressive phenotype. Current screening-guidelines suggest the use of prostate-specific antigen (PSA) only among BRCA2 carriers. Female carriers have extensive guidelines that include imaging. Our objective was to test the prevalence of PCa among BRCA carriers and examine screening strategies, using PSA and multiparametric magnetic resonance imaging (mpMRI). PATIENTS AND METHODS: We recruited men aged 40-70 years with BRCA1/2 germline mutations and no prior history of prostate biopsy. All men underwent an initial round of screening which included PSA, and prostate mpMRI. PSA was considered elevated using an age-stratified threshold of ≥1 ng/ml for 40-50 years of age, ≥2 ng/ml for 50-60 years of age, and 2.5 ng/ml for 60-70 years of age. Men with elevated PSA and/or suspicious lesion on mpMRI were offered a prostate biopsy. PSA levels, MRI findings, PCa incidence, and tumor characteristics were evaluated. Decision curve analysis was used to compare screening strategies. RESULTS: We recruited 188 men (108 BRCA1, 80 BRCA2), mean age 54 years (9.8). One hundred and ten (57%) had either elevated age-stratified PSA (75; 40%), a suspicious MRI lesion (67; 36%), or both (32; 17%). Of these, 92 (85%) agreed to perform a prostate biopsy. Sixteen (8.5%) were diagnosed with PCa; 44% of the tumors were classified as intermediate- or high-risk disease. mpMRI-based screening missed only one of the cancers (6%), while age-stratified PSA would have missed five (31%). Decision curve analysis showed that mpMRI screening, regardless of PSA, had the highest net benefit for PCa diagnosis, especially among men younger than 55 years of age. We found no difference in the risk of PCa between BRCA1 and BRCA2 (8.3% versus 8.7%, P = 0.91). Ninety percent had a Jewish founder mutation, thus the results cannot be generalized to all ethnic groups. CONCLUSIONS: PCa is prevalent among BRCA carriers. Age may affect screening strategy for PCa in this population. Young carriers could benefit from initial MRI screening. BRCA carriers aged older than 55 years should use PSA and be referred to mpMRI if elevated. TRIAL REGISTRATION: ClinicalTrial.gov ID: NCT02053805.

Sleep disorders and vascular responsiveness in patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is the most common systemic autoimmune disease characterized by chronic systemic inflammation. Half of the deaths of patients with RA are due to cardiovascular diseases (CVD), considered to be 1.5 to -2.0-fold that in the general population. Patients with RA also experience poor sleep, which by itself is associated with endothelial dysfunction, CVD events and sudden death. Our aim was to study the mechanistic pathways and the correlations between sleep efficiency and vascular reactivity of patients with RA. METHODS AND RESULTS: A prospective study that evaluated quality of sleep using ACTi Graphs, vascular inflammation and endothelial function of 18 patients with RA. Inflammation was studied by levels of E-selectin, intercellular adhesion molecule 1 (ICAM-1) and NO in serum. Endothelial function was studied using the brachial artery plethysmography method. Eighteen RA patients (aged 57.56 ± 13.55 years; 16 women) with a long-standing active RA: Eight patients had impaired sleep efficiency and 10 had a good sleep efficiency. Those who had an impaired sleep had larger baseline diameters of the brachial artery (0.39 ± 0.08 cm vs. 0.32 ± 0.04 cm; P = 0.02). Negative correlations were found between baseline brachial artery diameter and sleep efficiency (P = 0.01), and with NO level (P = 0.04). Stepwise regression found that brachial artery diameter at baseline and NO level could predict sleep efficiency (r2  = 0.543, P = 0.01). CONCLUSION: Vascular reactivity could predict quality of sleep in patients with RA. Quality of sleep may serve as an independent CVD risk factor in patients with RA.

Reporter gene-engineering of human induced pluripotent stem cells during differentiation renders in vivo traceable hepatocyte-like cells accessible.

Primary hepatocyte transplantation (HTx) is a safe cell therapy for patients with liver disease, but wider application is circumvented by poor cell engraftment due to limitations in hepatocyte quality and transplantation strategies. Hepatocyte-like cells (HLCs) derived from human induced pluripotent stem cells (hiPSC) are considered a promising alternative but also require optimisation of transplantation and are often transplanted prior to full maturation. Whole-body in vivo imaging would be highly beneficial to assess engraftment non-invasively and monitor the transplanted cells in the short and long-term. Here we report a lentiviral transduction approach designed to engineer hiPSC-derived HLCs during differentiation. This strategy resulted in the successful production of sodium iodide symporter (NIS)-expressing HLCs that were functionally characterised, transplanted into mice, and subsequently imaged using radionuclide tomography.

To proceed or not to proceed: ENT surgery in paediatric patients with acute upper respiratory tract infection.

BACKGROUND: Upper respiratory tract infection is the most common non-preventable cause of surgery cancellation. Consequently, surgeons and anaesthesiologists involved in elective ENT surgical procedures frequently face a dilemma of whether to proceed or to postpone surgery in affected children. METHODS: A literature review was conducted and a practical assessment algorithm proposed. CONCLUSION: The risk-benefit assessment should take into consideration the impact of postponing the surgery intended to bring relief to the child and the risks of proceeding with general anaesthesia in an inflamed airway. The suggested algorithm for assessment may be a useful tool to support the decision of whether to proceed or to postpone surgery.

Inhibition of inflammation may enhance nitric oxide availability in patients undergoing bariatric surgery for weight loss.

BACKGROUND: Weight loss surgery is the most effective treatment for morbid obesity. The mechanisms underlying the beneficial cardiovascular effects are poorly understood, although inhibition of inflammatory markers has been demonstrated. We hypothesized that anti-inflammatory and antioxidative stress reactions are responsible for the beneficial effects of bariatric surgery that have been shown in clinical trials. METHODS: The inflammatory system was studied by measuring mRNA levels of E-selectin, tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and in a cell line (HUVEC-CS) of human umbilical vein endothelial cells that were incubated for 4 h with pools of serum, collected before and 3 months after surgery, from 20 women who underwent bariatric surgery for weight loss. The oxidative stress pathway was examined by mRNA expression of NADPH oxidase (P22(phox) ), paraoxonase (PON2), superoxide dismutase 2 (SOD2), glutathione peroxidase (GPx) and catalase following incubation of the cells for 4 h with serum pools. The nitric oxide (NO) pathway was studied by measuring mRNA levels of inducible NOS and endothelial NOS and by determining nitrite and nitrate levels. To study the functional behaviour of endothelial cells under stress, primary human umbilical vein endothelial cells (PECs) were incubated with the serum pools for 48 h, with lipopolysaccharide (LPS) for the last 4 h. RESULTS: The inflammatory system: incubation of HUVEC-CS cells with serum from women who underwent bariatric surgery led to a significant decrease in mRNA expression of E-selectin and IL-6 postsurgery. Stimulation of PECs with LPS in the presence of serum from women who underwent bariatric surgery caused a more significant difference in E-selectin and TNF-α mRNA expression before and after surgery. The antioxidant system: incubation of HUVEC-CS cells with serum from women who underwent bariatric surgery did not lead to any difference in mRNA expression of P22(phox) , PON2, SOD2, GPx or catalase. Stimulation of PECs with LPS showed that obese women had higher levels of P22(phox) , PON2 and the antioxidant enzymes SOD2, GPx and catalase before and after surgery, compared to the control group. The NO pathway: HUVEC-CS cells incubated with serum from women who underwent bariatric surgery secreted higher nitrite/nitrate levels compared to presurgery serum (P = 0.04). CONCLUSIONS: Inhibition of inflammation and enhanced availability of NO 3 months after bariatric surgery could partly explain the beneficial effects of surgery for weight loss.

Severity of pneumococcal versus non-pneumococcal acute otitis media in children.

BACKGROUND: Pneumococcal acute otitis media (AOM) has been previously considered as a more severe disease than that caused by other otopathogens, based on clinical and/or otologic scores. We sought to test this hypothesis in the pneumococcal conjugated vaccine (PCV) era. METHODS: Children <6 years who presented with 'severe' AOM episodes with middle ear fluid (MEF) cultures during 2008-2013 were retrospectively identified. 'Severe' AOM episodes were considered if tympanocentesis was required or if spontaneous otorrhea was present. Data were extracted for demographics, clinical and laboratory tests. Children were categorised according to their PCV status as 'unimmunised' or 'PCV7/PCV13 immunised' and according to their MEF culture results into the 'pneumococcal' or the 'non-pneumococcal' group. Leukocytosis was defined as white blood cells (WBC) count >15 000/µL, and elevated C-reactive protein (CRP) level was considered as >50 mg/L. RESULTS: Of 295 eligible AOM episodes, 106 (36%) were culture positive. Children in the pneumococcal group (65, 61%) had a significantly higher WBC counts and higher CRP levels, were more often <2 years old and were more prone to complicate with acute mastoiditis (AM), compared to children in the non-pneumococcal group, P = 0.03, P = 0.02, P = 0.04 and P = 0.03, respectively. In the pneumococcal group, unimmunised children had higher WBC counts when compared with PCV13-immunised children (P = 0.04), but there were no appreciable differences in CRP levels between unimmunised and PCV7/PCV13-immunised children. CONCLUSION: Pneumococcal AOM is associated with higher leukocytosis and CRP levels than non-pneumococcal AOM. Circulating Streptococcus pneumoniae strains causing 'severe' AOM in PCV13-immunised children yielded lower inflammatory responses when compared with unimmunised children.

The role of oxidation in FSL-1 induced signaling pathways of an atopic dermatitis model in HaCaT keratinocytes.

Oxidative stress (OS) is common in inflammatory conditions and may be important in atopic dermatitis (AD) etiology. The aim of this project was to study the involvement of oxidation in FSL-1 (deacylated lipoprotein)-triggered signaling pathways leading to AD-typical cytokine expression in HaCaT keratinocytes. HaCaT keratinocytes, pretreated with the inhibitor to OS N-acetylcysteine (NAC), were exposed to FSL-1, a stimulator of AD-related cytokines. Cytokines expression was studied by real time polymerase chain reaction (PCR); nuclear factor-kappa B (NF-κB) and p38 mitogen activated protein kinase (MAPK) activities were studied by western blotting; and the oxidative state of cells was determined by the dichlorofluorescein (DCF) assay. We found that endogenous OS in keratinocytes appeared 4 h after FSL-1 administration. OS activated NF-κB, but not p38 MAPK, and the inhibition of OS reduced FSL-1 induced interleukin (IL) 33, thymic stromal lymphopoietin (TSLP) and TNFα mRNA expression. We conclude that FSL-1 triggers an OS reaction in HaCaT keratinocytes, which is probably a secondary event affecting the expression of specific AD typical cytokines, possibly through the NF-κB pathways. This role of OS in the inflammatory response in AD is worth further investigating.

18F-sodium fluoride uptake is a marker of active calcification and disease progression in patients with aortic stenosis.

BACKGROUND: 18F-Sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) are promising novel biomarkers of disease activity in aortic stenosis. We compared 18F-NaF and 18F-FDG uptake with histological characterization of the aortic valve and assessed whether they predicted disease progression. METHODS AND RESULTS: Thirty patients with aortic stenosis underwent combined positron emission and computed tomography using 18F-NaF and 18F-FDG radiotracers. In 12 patients undergoing aortic valve replacement surgery (10 for each tracer), radiotracer uptake (mean tissue/ BACKGROUND: =0.65; P=0.04) and osteocalcin (r=0.68; P=0.03) immunohistochemistry. There was no significant correlation between 18F-FDG uptake and CD68 staining (r=-0.43; P=0.22). After 1 year, aortic valve calcification increased from 314 (193-540) to 365 (207-934) AU (P<0.01). Baseline 18F-NaF uptake correlated closely with the change in calcium score (r=0.66; P<0.01), and this improved further (r=0.75; P<0.01) when 18F-NaF uptake overlying computed tomography-defined macrocalcification was excluded. No significant correlation was noted between valvular 18F-FDG uptake and change in calcium score (r=-0.11; P=0.66). CONCLUSIONS: 18F-NaF uptake identifies active tissue calcification and predicts disease progression in patients with calcific aortic stenosis. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01358513.

Anterior shoulder instability associated with coracoid nonunion in patients with a seizure disorder.

BACKGROUND: An association between coracoid fracture and glenohumeral instability with both a seizure disorder and the subsequent development of coracoid nonunion has not previously been recognized. This is clinically important as patients with a seizure disorder and glenohumeral instability frequently require a primary osseous reconstructive procedure, such as coracoid osteotomy and transfer to the anterior glenoid rim (the Bristow-Latarjet procedure), to address glenoid osseous deficiency. We report on coracoid fracture nonunion in five patients with a seizure disorder and anterior glenohumeral instability and discuss the implications for surgical treatment. METHODS: Coracoid fracture was specifically sought on three-dimensional reconstructions of computed tomography scans in a consecutive series of 234 patients presenting to our unit with recurrent anterior instability. In addition to demographic data, we specifically sought information on any history of shoulder injury, the mechanism of injury, or previous seizure activity in these patients. In patients with a coracoid fracture or nonunion viewed to be at high risk of failure with a soft-tissue procedure, an open osseous reconstructive procedure was performed. The type of operative procedure was determined by the location of the nonunion. RESULTS: We identified six coracoid fracture nonunions in association with anterior glenohumeral instability in five patients (mean age, 26.8 years; range, twenty-four to thirty years). All patients had instability occurring in association with seizures. In the four shoulders with the anatomic location of the coracoid nonunion at its so-called elbow, a standard Bristow-Latarjet procedure was performed. In the two shoulders in which the nonunion was more distal, an Eden-Hybbinette procedure was performed. CONCLUSIONS: We recommend having a high index of suspicion of coracoid fracture when treating patients with a seizure disorder who have anterior glenohumeral instability. In these patients, preoperative computed tomographic images allow the diagnosis of a coracoid nonunion to be made prior to surgery and help to determine whether there is sufficient intact coracoid bone to allow a Bristow-Latarjet procedure to be performed.

Fetal radiofrequency radiation exposure from 800-1900 mhz-rated cellular telephones affects neurodevelopment and behavior in mice.

Neurobehavioral disorders are increasingly prevalent in children, however their etiology is not well understood. An association between prenatal cellular telephone use and hyperactivity in children has been postulated, yet the direct effects of radiofrequency radiation exposure on neurodevelopment remain unknown. Here we used a mouse model to demonstrate that in-utero radiofrequency exposure from cellular telephones does affect adult behavior. Mice exposed in-utero were hyperactive and had impaired memory as determined using the object recognition, light/dark box and step-down assays. Whole cell patch clamp recordings of miniature excitatory postsynaptic currents (mEPSCs) revealed that these behavioral changes were due to altered neuronal developmental programming. Exposed mice had dose-responsive impaired glutamatergic synaptic transmission onto layer V pyramidal neurons of the prefrontal cortex. We present the first experimental evidence of neuropathology due to in-utero cellular telephone radiation. Further experiments are needed in humans or non-human primates to determine the risk of exposure during pregnancy.

Mutual interaction of special phytoestrogenic compounds, their synthetic carboxy-derivatives and the less-calcemic vitamin D analog activities in human derived female cultured osteoblasts.

Cultured female-derived human bone cells (hObs) responded by different parameters to different phytoestrogenic and vitamin D compounds. Pre- and post-menopausal hObs express ERα and ERß mRNA with higher abundance of ERα. Pre-treatment with the less-calcemic vitamin D analog JKF 1624F(2)-2 (JKF) upregulated responsiveness to estrogens via modulation of ERs expression. These estrogenic compounds induce the expression and activity of 25 hydroxy-vitamin D(3)-1α hydroxylase (1OHase). We now analyzed the effects of carboxy-genistein (cG), carboxy-biocainin A (cBA) and carboxy-daidzein (cD), of BA, D or G and of licorice derived compounds glabridin (Glb) and glabrene (Gla) and estradiol-17ß (E(2)) on DNA synthesis, creatine kinase specific activity (CK), intracellular and membranal E(2) binding and their modulations by JKF in hObs. We also analyzed modulation by phytoestrogenic compounds of 1OHase mRNA expression and activity. We showed that: (1) all compounds stimulated DNA synthesis and CK. (2) JKF and all estrogenic compounds modulated ERα and ERß mRNA expression. (3) Pre-treatment with JKF increased DNA synthesis and CK responses only to E(2), D, G and Gla. (4) JKF increased the intracellular competitive binding only of E(2), D and G. (5) JKF abolished the membranal binding of all protein-bound estrogens. (6) JKF and all estrogenic compounds except the protein-bound ones up-regulated 1OHase expression and activity. In conclusion phytoestrogens and their analogs increase DNA synthesis and CK, and lead to increased production of 1,25(OH)(2)D(3) in hObs, while pre-treatment with JKF modulates the effect of estrogenic compounds via regulation of ERs mRNA expression in a yet unclear mechanism.

Bisphenol-A exposure alters endometrial progesterone receptor expression in the nonhuman primate.

OBJECTIVE: To evaluate the effect of bisphenol-A (BPA), a xenoestrogen endocrine disruptor, on endometrial P receptor (PR) expression in nonhuman primates and human cells. DESIGN: Controlled trial in primates. SETTING: University. ANIMAL(S): African green monkeys. INTERVENTION(S): After oophorectomy, BPA (50 µg/kg/d), E(2), both, or vehicle control were administered. Estradiol and BPA were used in Ishikawa cells. MAIN OUTCOME MEASURE(S): Progesterone receptor expression using immunohistochemistry and quantitative polymerase chain reaction. RESULT(S): Progesterone receptor expression was increased in E(2)-treated primates compared with controls. Exposure to the combination of E(2) and BPA resulted in decreased PR expression compared with E(2) exposure alone. In Ishikawa cells treated with E(2), PR expression increased 5.1-fold; however, when Ishikawa cells were simultaneously treated with E(2) and BPA, PR expression was decreased to 0.6-fold that of cells treated with E(2) alone. CONCLUSION(S): Bisphenol-A alone functions as a weak estrogen. However, when administered with E(2), BPA diminishes E(2)-induced PR expression. The estrogen-like effect of BPA reported in exposed humans may be mediated by PR blockade and a resultant decrease in the estrogen inhibition normally imparted by P. Diminished PR expression may underlie previous reports linking BPA exposure to endometrial dysfunction in humans.

In utero exposure to diethylstilbestrol (DES) or bisphenol-A (BPA) increases EZH2 expression in the mammary gland: an epigenetic mechanism linking endocrine disruptors to breast cancer.

Diethylstilbestrol (DES) and bisphenol-A (BPA) are estrogen-like endocrine-disrupting chemicals that induce persistent epigenetic changes in the developing uterus. However, DES exposure in utero is also associated with an increased risk of breast cancer in adult women. Similarly, fetal exposure to BPA induces neoplastic changes in mammary tissue of mice. We hypothesized that epigenetic alterations would precede the increased risk of breast neoplasia after in utero exposure to endocrine disruptors. Enhancer of Zeste Homolog 2 (EZH2) is a histone methyltransferase that has been linked to breast cancer risk and epigenetic regulation of tumorigenesis. We examined the effect of BPA and DES on EZH2 expression and function in MCF-7 cells and in mammary glands of mice exposed in utero. DES and BPA treatment approximated human exposure. EZH2 functional activity was assessed by measuring histone H3 trimethylation. Treatment of MCF-7 cells with DES or BPA led to a 3- and 2-fold increase in EZH2 mRNA expression, respectively (p < 0.05) as well as increased EZH2 protein expression. Mice exposed to DES in utero showed a >2-fold increase in EZH2 expression in adult mammary tissue compared with controls (p < 0.05). EZH2 protein was elevated in mammary tissue of mice exposed to DES or BPA. Histone H3 trimethylation was increased in MCF-7 cells treated with BPA or DES. Similarly, mice exposed to BPA or DES in utero showed increased mammary histone H3 trimethylation. Developmental programming of EZH2 is a novel mechanism by which in utero exposure to endocrine disruptors leads to epigenetic regulation of the mammary gland.

The response of creatine kinase specific activity in rat pituitary to estrogenic compounds and vitamin d less-calcemic analogs.

We examined the response of rat female pituitary at different metabolic stages to treatments with estrogenic compounds and vitamin D analogs. Immature or ovariectomized (Ovx) female rats responded by increased creatine kinase specific activity (CK) to estradiol-17beta (E(2)), genistein (G), daidzein (D), biochainin A (BA), quecertin (Qu), carboxy- G (cG), carboxy- BA (cBA), and raloxifene (Ral). The response was inhibited when Ral was injected together with the estrogens. CK was increased when hormones were injected daily into Ovx rats for 4 different time periods. Pretreatment with the less-calcemic vitamin D analogs JK 1624 F(2)-2 (JKF) or QW 1624 F(2)-2 (QW) followed by estrogenic injection resulted in increased response and sensitivity to E(2) and loss of inhibition of E(2) by Ral. CK was also increased by feeding with E(2) or licorice or its components dose- and time- dependent in immature or Ovxrats. Diabetic female rats did not respond to increased doses of E(2). In conclusion, rat female pituitary is estrogens-responsive organ, suggesting to considerits response for HRT in postmenopausal women for both beneficial and hazardous aspects.

Defining the proliferative phase endometrial defect.

OBJECTIVE: To evaluate proliferative phase endometrial development in a heterogeneous infertility population. DESIGN: Retrospective study. SETTING: University-based infertility practice. PATIENT(S): Two hundred forty-six treatment cycles. INTERVENTION(S): Clomiphene citrate or FSH ovarian stimulation, followed by IUI or IVF. MAIN OUTCOME MEASURE(S): Endometrial thickness according to transvaginal ultrasonography; clinical pregnancy rate. RESULT(S): Endometrial growth began from a nadir of approximately 4.5 mm on cycle day 4 and increased linearly to a plateau of approximately 10 mm on cycle day 9. This same pattern was observed in all cycles, regardless of pregnancy, drug, or underlying diagnosis. Follicle-stimulating hormone-stimulated cycles showed a significantly increased endometrial thickness compared with clomiphene citrate cycles (10.1 vs. 8.3 mm). Maximum endometrial thickness achieved showed a correlation with age, body mass index, and maximum E(2) level. Subjects who carried a primary diagnosis of polycystic ovary syndrome, endometriosis, or recurrent pregnancy loss all achieved a significantly lower peak endometrial thickness than control subjects. There was a trend toward increased endometrial thickness in cycles resulting in pregnancy compared with those not (10.1 vs. 9.6 mm, respectively). CONCLUSION(S): Endometrial development follows a predictable pattern, with a plateau in growth at cycle day 9. Diseases associated with infertility manifest a proliferative phase defect that can be recognized clinically.

Does hysteroscopy affect prognosis in apparent early-stage endometrial cancer?

The objective of the study was to compare the outcome measures of patients with endometrial adenocarcinoma diagnosed by endometrial biopsy, uterine curettage, or hysteroscopy. Medical records of 392 women diagnosed with apparent early-stage endometrial adenocarcinoma were reviewed. Data concerning the mode of diagnosis, histologic type and grade, surgical stage, peritoneal washings and lymph nodes status, and patient's outcome were retrieved. During the study period, 99 (25.3%) cases were diagnosed by endometrial biopsy, 193 (49.2%) by uterine curettage, and 100 (25.5%) by hysteroscopy. There were 347 (88.5%) cases of endometrioid adenocarcinoma and 45 (11.5%) of poor histologic types, including serous papillary, clear cell, and small cell cancer. Three hundred and sixteen (80.6%) patients had stage I disease, 8 (2.0%) stage II, and 68 (17.4%) stage III. Peritoneal cytology was positive in only one case. Recurrent disease occurred in 6.9% patients, of which 50% had local recurrence and 50% had distant. Recurrent disease was found in 15.2% patients diagnosed by endometrial biopsy, in 4.7% where uterine curettage was used, and in 5% when hysteroscopy was applied. No statistically significant difference in the survival rate between the different diagnostic methods applied was found, although a higher recurrence rate was noted following endometrial biopsy. After a median follow-up time of 25 months for patients undergoing hysteroscopy, there was no difference in recurrence rates and/or overall survival compared to other diagnostic procedures implying that hysteroscopy can be safely used in the diagnosis of endometrial cancer.

Estrogen-like activity of glabrene and other constituents isolated from licorice root.

Licorice root extract and its major isoflavan, glabridin, exhibited varying degrees of estrogen receptor (ER) agonism in different tissues in vitro and in vivo. Animals fed with licorice extract, compared with estradiol and glabridin, showed an increase in creatine kinase (CK) activity, a known marker for estrogen responsive genes, which was higher than expected from the levels of glabridin in the extract. This led us to test for other components that may contribute to this strong estrogen agonist activity. Results indicated that glabrene and isoliquiritigenin, (2',4',4-three hydroxy chalcone) (ILC) in the licorice extract can bind to the human ER with higher affinity (IC50, 1 and 0.5 microM) than glabridin (IC50, 5 microM). The stimulatory effects of glabrene in vivo were tissue specific and similar to those of estradiol. The effect of increasing concentrations of glabrene and ILC on the growth of breast tumor cell were biphasic. Both showed an ER-dependent growth-promoting effect at low concentrations (10 nM-10 microM), and ER-independent antiproliferative activity at concentrations >15 microM. This is the first study to indicate that glabrene, an isoflavene exerted varying degrees of ER agonism in different tissues.

Paradoxical interactions among estrogen receptors, estrogens and SERMS: mutual annihilation and synergy.

The phenomenon of mutual annihilation of action between 17beta estradiol (E(2)) and a selective estrogen receptor modulator (SERM), previously described in prepubertal rat diaphysis, epiphysis and uterus, has been investigated in ROS 17/2.8 rat osteoblastic cells and in transiently co-transfected cells in culture. In ROS 17/2.8 cells, the estrogen-induced marker enzyme creatine kinase B (CKB) was stimulated by raloxifene, tamoxifen and tamoxifen methiodide to a specific activity equal to or greater than that induced by 10 nM E(2). However, when a fully inhibitory dose of any of these SERMS was given simultaneously with E(2), no stimulation of CK activity resulted. Therefore, SERMS can be full agonists when acting alone, but complete antagonists to a super-physiological dose of estrogen. It is expected that excess tamoxifen would prevent the action of a SERM, but that the agonist activity of a SERM is abolished by 1000-fold less estrogen is a phenomenon without obvious explanation by classical pharmacology of competitive inhibition. To probe the mechanism of this interaction further, a ckb-CAT reporter plasmid, plus the human receptor expression plasmid, HEO, was transfected transiently into several cell types. In MCF-7 cells, a 1:10 ratio of E(2) to tamoxifen produced mutual annihilation, but the same ratio in ROS 17/2.8 or HeLa cells led to synergistic stimulation. In HeLa cells, co-transfected with the more efficient wild-type estrogen receptor plasmid, HEGO, synergy was demonstrated only at sub-saturation levels of HEGO. We speculate that, in the presence of estradiol and a SERM, not only active homodimers would be formed, but also hetero-dimers of estrogen-liganded and tamoxifen-liganded receptor monomers, depending on the molar ratio of their ligands and their relative affinities. The resulting hetero-dimer conformation would change the specific receptor surface for interactions with the growing number of co-activators and co-repressors, structural changes which could help to explain the mutual annihilation and synergy phenomena and their cell selectivity.