Synthesis and structure guided evaluation of estrogen agonist and antagonist activities of some new tetrazolyl indole derivatives

Several regioisomeric tetrazolyl indole derivatives with structurally modified alkyl substituents at the tetracyclic indole nitrogen containing N-ethyl amino tetrazole moiety have been synthesized and screened for their ER binding affinity, agonist (estrogenic), antagonist (antiestrogenic) and anti-implantation activities. N-2 regioisomers were found to be moderately antagonists and one compound showed 100% contraceptive efficacy at 10 mg/kg dose. Molecular docking studies carried out in comparison to estradiol and raloxifene showed different binding modes of the two regioisomers to the binding site.     

Lymphoma with tuberculous granulomas

Chronic granulomatous inflammation is a common finding in lymphoproliferative disorders (LPDs), but it is important to exclude coexisting mycobacterium tuberculosis (MTB) especially in patients from areas of high endemicity. This case emphasizes the relevance of performing MTB culture on bone marrow exhibiting LPD and concomitant granulomas.     

Vitamin K Supplementation for Prevention of Vascular Calcification in Chronic Kidney Disease Patients: Are We There Yet?

Chronic Kidney Disease (CKD) patients are at high risk of presenting with arterial calcification or stiffness, which confers increased cardiovascular mortality and morbidity. In recent years, it has become evident that VC is an active process regulated by various molecules that may act as inhibitors of vessel mineralization. Matrix Gla Protein (MGP), one the most powerful naturally occurring inhibitors of arterial calcification, requires vitamin K as a co-factor in order to undergo post-translational γ-carboxylation and phosphrorylation and become biologically active. The inactive form of MGP (dephosphorylated, uncarboxylated dp-ucMGP) reflects vitamin K deficiency and has been repeatedly associated with surrogate markers of VC, stiffness, and cardiovascular outcomes in CKD populations. As CKD is a state of progressive vitamin K depletion and VC, research has focused on clinical trials aiming to investigate the possible beneficial effects of vitamin K in CKD and dialysis patients. In this study, we aim to review the current evidence regarding vitamin K supplementation in uremic patients.     

Über das Durch Kaolin Oder Stärke Erzeugte Sogenannte „Anaphylatoxin“

Ohne Zusammenfassung     

Kolloidchemische Analyse der Anaphylaktischen Präcipitation

Ohne Zusammenfassung     

Tri-n-butyltin Increases Intracellular Ca2+ in Mouse Thymocytes: A Flow-Cytometric Study Using Fluorescent Dyes for Membrane Potential and Intracellular Ca2+

Abstract: Effects of tri-n-butyltin (TBT) on mouse thymocytes were examined using a flow-cytometer and fluorescent dyes for membrane potential and intracellular Ca²⁺ ([Ca²⁺]_i). TBT at concentrations from 1 × 10^-7 M to 3 × 10^-7 M caused hyperpolarization in thymocytes during 30 min. after drug application in a time- and dose-dependent manner. Further increase in TBT concentration (to 1 × 10^-6 M) made hyperpolarization of thymocytes more profound within 5 min. after application, thereafter gradually depolarized them during the next 25 min. TBT at 3 × 10^-8 M or more (up to 1 × 10^-6 M) increased the [Ca²⁺]_i of thymocytes. After reaching maximum [Ca²⁺]_i at the various TBT concentrations used within 5 min. after drug application, the [Ca²⁺]_i slightly decreased in a time-dependent manner. Effects of TBT on membrane potential and the [Ca²⁺]_i were greatly reduced under nominal external Ca²⁺ -free condition. Results suggest that TBT can promote Ca²⁺ -influx to thymocytes, resulting in hyperpolarization by activation of Ca²⁺ -dependent K⁺ current. The increase in [Ca²⁺]_i by TBT may be related to its cytotoxic action on thymocytes.     

Lack of electron microscopy hinders correct renal biopsy diagnosis: A study from India

Electron microscopy (EM) is performed routinely on all native kidney biopsies in the western world. However, in India, it is not regularly performed due to non-availability and financial constraints. The aim of this prospective study was to evaluate the usefulness of routinely performing EM on native kidney biopsies. In order to eliminate selection bias, all consecutive native kidney biopsies were included in this study, provided they had adequate tissue for light, immunofluorescence (IF), and EM. The biopsies were reported on the basis of light and IF microscopy. EM was performed on each case by another pathologist who also independently reviewed the light microscopic slides and IF images. The findings were then reviewed to assess how the ultrastructural features contributed to the primary diagnosis and assigned to one of the following categories: 1. Crucial for diagnosis, 2. Important contribution, or 3. Not required. Of the 115 cases evaluated, EM was crucial in 12% of the cases. In 20% of the cases, it provided important confirmatory information and in the remaining 68% cases, EM was not considered required. This study supports the use of EM as a routine diagnostic tool in the evaluation of native kidney biopsies. There is an urgent need for availability and accessibility of EM in our country.     

Modulation of estrogen action during preimplantation period and in immature estradiol-primed rat uterus by anti-implantation agent, ormeloxifene

Studies were undertaken to evaluate the influence of estrogen antagonist-cum anti-implantation agent, ormeloxifene, on 17β-hydroxydsteroid dehydrogenase (17β-HSD) activity and estrogen action in rat uterus during preimplantation period and to examine its ability to induce progesterone receptor (PR) in immature rat model. A group of female rats received orally a contraceptive dose of 1.25 mg/kg of ormeloxifene on Day 1 postcoitum (pc). Rats were sacrificed on Days 3, 4 and 5 pc, and uterine tissues were processed for enzymatic, estrogen receptor and estradiol (E₂) estimations. Immature ovariectomized rats received ormeloxifene, subcutaneously for 3 days at various doses in the absence or presence of estradiol, and uterine PR levels were measured using ³H-R5020 as radioligand.

Results revealed that ormeloxifene treatment caused a marked increase in enzyme activity of 17β-HSD on Days 3, 4 and 5 pc as compared to respective controls. Further, total uterine estrogen receptors as estimated by exchange assay showed a noticeable decrease on Days 4 (35%) and 5 (>80%) pc in ormeloxifene-treated groups. The results correlated well with a decrease in tissue E₂ levels. In immature rats, ormeloxifene caused a dose-dependent increase in cytosolic PR levels; ormeloxifene given along with E₂ (0.1 μg) for 3 days caused a significant reduction in concentration of PRs at 10 μg and higher doses.

Ormeloxifene also induced ³H-progesterone (P) uptake by immature rat uterus. However, in the presence of E₂, it significantly reduced ³H-P uptake. The in vitro competitive binding experiments did not reveal any displacement of ³H-R5020 either by ormeloxifene or by its hydroxy derivative from PR. The results suggest that in addition to its competitive antagonism at estrogen receptor level, ormeloxifene enhances the inactivation of intracellular E₂ to estrone, a biologically less active form, thus declining estrogen receptor pool. Moreover, it causes indirect anti-progestational effects in the uterus by virtue of its anti-estrogenic profile rather than by blocking the PRs.     

Nucleotide correlation between HAV isolates from human patients and environmental samples

Hepatitis A disease is endemic in Albania even though records from the Medical Authority show outbreaks involving only limited numbers of people. In the city of Lac, 200 people became ill following an outbreak of hepatitis A started on November 2002. The age distribution of the cases shows a peak in the age group 5-9 (43.5%) followed by the age group 10-14 (28%) and the age group 1-4 (18%). No cases were recorded in the age group 0-1. Drinking water and sewage samples were collected, using electropositive cartridges, during the outbreak. Rotavirus was identified by RT-PCR in two out of five drinking water samples; however, all the samples tested negative for HAV and astrovirus. Rotavirus was also identified in three out of five sewage samples from which four were HAV positive. HAV-RNA was identified in 28 (62.2%) out of 45 IgM anti-HAV positive sera collected during the outbreak. Genotype IA was expressed from all the amplified samples. Sequence analysis of the overlapping VP1-2A region shows 97-99% homology with three Italian strains IT-SCH-00, IT-ZAM-01, and IT-CAP-00 and one Spanish strain (Sa 30/06/95), whereas the phylogenetic tree built from the 168 bp sequence of the VP1-2A shows four clusters, one including 24 out of 28 RT-PCR positive sera. Considering the deduced amino acid sequence, only one substitution was identified and reported previously for genotype IB.