Progesterone Receptor Levels Independently Predict Survival in Endometrial Adenocarcinoma

Estrogen receptor (ER) and progesterone receptor (PR) contents were determined by biochemical (dextran charcoal-coated (DCC) assay) and immunohistochemical (ICA) methods in biopsies from 145 primary endometrial adenocarcinomas and those with eligible receptor measurements were analyzed with respect to correlations to cancer-specific survival in a multivariate analysis including histopathological characteristics. Median patient follow-up time was 67 months with 18 cancer deaths. The PR-DCC and ER-DCC values were dichotomized according to levels previously found by us to correspond to the best agreement between receptor status as determined by the DCC and ICA methods (130 fmol/mg cytosol protein for ER, 114 fmol/mg for PR). Using these thresholds, we found by multivariate analysis that “high” PR-DCC levels (>114 fmol/mg) correlated significantly (P= 0.004) with survival, independent of stage risk group (Ia + b vs Ic-IV). Patient age and histologic grade were prognostic factors in a univariate setting, but these parameters were eliminated in the multivariate model. While the PR-ICA scores also correlated significantly and independently with survival, the predictive effect of PR-ICA positivity alone could not be statistically evaluated due to the number of cases with eligible ICA values. However, we suggest that owing to a close correlation between DCC and ICA results, PR-ICA status may provide significant prognostic information when DCC measurements are not available.     

Monocytes and macrophages in malignant melanoma. II. Lysis of antibody-coated human erythrocytes as an assay of monocyte function

Peripheral blood mononuclear cells will lyse antibody-treated human erythrocytes. Using Group A red cells and a hyperimmune anti-A1 serum, we have devised a microassay for the cytolytic capacity of mononuclear cell suspensions. The effector cells responsible for red-cell lysis are mononuclear, adherent and phagocytic, and their activity is blocked by aggregated IgG. Their presence correlates well with non-specific esterase-containing cells and we conclude that they are monocytes. Dose-response curves of red-cell lysis plotted against numbers of monocytes were used to derive a simple parameter expressing the number of monocytes needed to lyse 15% of the 51Cr-labelled red cells. The assay was applied to a group of 27 normal controls and 36 patients with a histologically proven diagnosis of malignant melanoma. The results indicate that monocytes from patients show significantly greater lytic activity than those from the controls. These data suggest that monocytes from cancer patients are in some way activated, and that other defects in monocyte function which have been detected in cancer patients (defective chemotaxis and maturation) may be associated with monocyte "activation".     

Sudden Visual Deterioration as the First Symptom of Chronic Kidney Failure

Purpose

We report here a unique case of a sudden loss of vision as the first symptom of an advanced chronic nephropathy.

Methods and Results

A 25-year-old man was referred to the Department of Ophthalmology with sudden visual deterioration presumptively diagnosed as bilateral retinitis. The patient had never been under any medical care before and had never had any clinical signs of any chronic disease. He underwent an ophthalmic examination with optical coherence tomography (OCT). Based on the clinical features, OCT scans and systemic blood pressure (BP) assessment (225/145 mm Hg), the patient was definitely diagnosed with hypertensive retinopathy and choroidopathy due to hypertensive crisis. After urgent diagnostic procedures, the patient was diagnosed with a chronic kidney disease at stage 5 in the course of chronic glomerulonephritis. Immediately, a renal replacement therapy was started and the patient was qualified for renal transplantation.

Conclusion

Adolescents with an unclear picture of retinal lesions, who have neither a history nor clinical signs of a systemic disease, should undergo careful systemic screening with BP assessment. A sudden deterioration of vision may be the first symptom of a previously undiagnosed severe systemic disease (very rare chronic) that requires immediate treatment.Key Words: Hypertensive crisis, Hypertensive choroidopathy, Hypertensive retinopathy, Chronic renal failure     

Circulating levels of incretin hormones and amylin in the fasting state and after oral glucose in GH-deficient patients before and after GH replacement: a placebo-controlled study

OBJECTIVE: Hyperinsulinemia in association with GH excess is considered a compensatory response to insulin resistance, but the possibility of alternative insulinotropic mechanisms has not been investigated in vivo. It is also unknown how GH influences the secretion from pancreatic beta-cells of amylin, a peptide which regulates prandial glucose homeostasis and may be linked to development of beta-cell dysfunction. We therefore measured plasma concentrations of two gut insulinotropic hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulin-releasing peptide (GIP), and total as well as non-glycosylated amylin, in 24 GH-deficient adults before and after 4 months of GH replacement (daily evening injections of 2 IU GH/m). DESIGN: Double-blind, placebo-controlled, parallel study. METHODS: All participants underwent an oral glucose tolerance test (OGTT) at 0 and 4 months. RESULTS: A 33% suppression of fasting GLP-1 concentrations was measured in the GH group at 4 months (P=0.02), whereas a non-significant increase occurred in the placebo group (P=0.08). Fasting levels of GIP and amylin did not change significantly after 4 months in either group. The incremental response in GLP-1 during the OGTT was significantly lower after GH treatment as compared with both baseline (P=0.02) and the response in the placebo group (P=0. 03). The stimulation of GIP secretion following OGTT was similar on all occasions. The OGTT-induced incremental response in non-glycosylated amylin was moderately elevated after GH treatment as compared with placebo (P=0.05). Plasma concentrations of glucose and insulin, both in the fasting state and after the OGTT, were higher after GH treatment, but the ratio between amylin and insulin remained unchanged. CONCLUSIONS: GH-induced hyperinsulinemia is accompanied by proportionate elevations in amylin concentrations and a blunting of gut GLP-1 secretion. The mechanisms underlying the suppression of GLP-1 remain to be elucidated.     

EFTUD2 missense variants disrupt protein function and splicing in mandibulofacial dysostosis Guion‐Almeida type

Pathogenic variants in the core spliceosome U5 small nuclear ribonucleoprotein gene EFTUD2/SNU114 cause the craniofacial disorder mandibulofacial dysostosis Guion‐Almeida type (MFDGA). MFDGA‐associated variants in EFTUD2 comprise large deletions encompassing EFTUD2, intragenic deletions and single nucleotide truncating or missense variants. These variants are predicted to result in haploinsufficiency by loss‐of‐function of the variant allele. While the contribution of deletions within EFTUD2 to allele loss‐of‐function are self‐evident, the mechanisms by which missense variants are disease‐causing have not been characterized functionally. Combining bioinformatics software prediction, yeast functional growth assays, and a minigene (MG) splicing assay, we have characterized how MFDGA missense variants result in EFTUD2 loss‐of‐function. Only four of 19 assessed missense variants cause EFTUD2 loss‐of‐function through altered protein function when modeled in yeast. Of the remaining 15 missense variants, five altered the normal splicing pattern of EFTUD2 pre‐messenger RNA predominantly through exon skipping or cryptic splice site activation, leading to the introduction of a premature termination codon. Comparison of bioinformatic predictors for each missense variant revealed a disparity amongst different software packages and, in many cases, an inability to correctly predict changes in splicing subsequently determined by MG interrogation. This study highlights the need for laboratory‐based validation of bioinformatic predictions for EFTUD2 missense variants.     

Silymarin from Milk Thistle Fruits Counteracts Selected Pathological Changes in the Lenses of Type 1 Diabetic Rats

Diabetes is a metabolic disease affecting many tissues and organs. The main etiological factor for diabetic complications is hyperglycemia and subsequent pathologies, such as oxidative stress. One of the organs susceptible to the development of diabetic complications is the eye with all of its elements, including the lens. The aim of this study was to evaluate the effect of silymarin, an extract obtained from milk thistle fruit husks, on the oxidative stress markers in the lenses of type 1 diabetic rats. The study was performed on male rats in which type 1 diabetes was induced with 60 mg/kg streptozotocin injection. Diabetic animals were treated via an intragastric tube with silymarin at 50 and 100 mg/kg doses for four weeks. Multiple oxidative stress and polyol pathway-related parameters were measured in the lenses, and auxiliary biochemical tests in the serum were conducted. Diabetes induced severe pathological changes both in the lenses and the serum, and silymarin counteracted several of them. Nevertheless, the qualitative analyses encompassing all tested parameters indicate that silymarin slightly improved the overall state of diabetic animals. Upon the obtained results, it can be concluded that silymarin reveals a faint positive effect on the lenses in type 1 diabetic rats.     

Biochemical and immunohistochemical estrogen and progesterone receptors in adenomatous hyperplasia and endometrial carcinoma: correlations with stage and other clinicopathologic features.

OBJECTIVE: This study investigates clinicopathologic associations of estrogen and progesterone receptor content in endometrial carcinoma. STUDY DESIGN: One hundred fifty-two patients with endometrial cancer and 12 with adenomatous hyperplasia were included. Dextran-coated charcoal receptor assay and immunohistochemical analysis were used. The immunohistochemical analysis receptor content was estimated semiquantitatively by a total and a cancer immunohistochemical histologic score. Multiple regression analysis was used in testing independence of established correlations. RESULTS: Estrogen and progesterone receptor dextran-coated charcoal values and immunohistochemical histologic scores correlated inversely (p < 0.001) with International Federation of Gynecology and Obstetrics grade of tumor. An inverse correlation (p < 0.0001) between clinical stage and dextran-coated charcoal values was independent of International Federation of Gynecology and Obstetrics grade. Age of patient, years since menopause, and previous estrogen treatment were not related to receptor content. In adenomatous hyperplasia high progesterone receptor levels were seen. CONCLUSION: The inverse correlation between clinical stage of endometrial carcinoma and content of estrogen and progesterone receptors may reflect tumor biologic behavior.     

Influence of nitrogen status on the bioconcentration of hydrophobic organic compounds to Selenastrum capricornutum

Changes in algal nitrogen status that increase algal lipid content also affect the bioconcentration of hydrophobic organic compounds (HOCs). Bioconcentration factors (BCFs) for several HOCs increased up to nine times as the total algal lipid content of the green algae Selenastrum carpricornutum increased from 17 to 44% of the algal dry weight as a consequence of nitrogen starvation. An increase in total lipid from 17 to 44% should theoretically increase the BCFs by a factor of 2.6. BCFs for PCB 31, PCB 49, PCB 153, and DDT increased with maximum lipid content by factors of 6.3, 8.9, 8.9, and 6.6, respectively, thus more than theoretically predicted from the lipid normalization of BCFs obtained at exponential growth phase (17% total lipid for S. carpricornutum), whereas BCFs for PCB 105, phenanthrene, and 4-chloroaniline increased at 44% lipid content, only by factors of 1.5, 1.5, and 2.5, respectively, and thus less than or equal to the theoretical prediction. Lipid-class normalization of BCFs did not reveal significant information beyond that available from normalizing to total lipid.     

The role of therapeutic use of interleukin-2 in HIV infection

Interleukin-2 (IL-2) is a cytokine produced by lymphocytes T CD4+, T CD8+ and NK cells. IL-2 increases the number of lymphocytes T and prolongs their survival and has extensive immunomodulatory effect. High levels of IL-2 are observed during asymptomatic phase of HIV infection (TH-1 dependent cytokine) and low levels are observed during progression of immunodeficiency. IL-2 inhibits apoptosis of CD4+ T cells, improves NK cells activity, has influence on production of soluble antiviral factor (CAF) which inhibits viral activity etc. That is why IL-2 has been introduced to the treatment of HIV infection along with highly active antiretroviral therapy (HAART). High T CD4+ cells count predicts long survival of HIV infected individual. Phase III clinical trials concerning IL-2 are now performed and the preliminary results are promising. Polish centers also take part in the ESPRIT study. Adverse events of various severity are seen in patients under treatment (anti inflammatory drugs are required). The symptoms usually resolve within a few days after IL-2 therapy is stopped.