Fruitful Pregnancy Outcome in a Case of Eisenmenger Syndrome With Severe Pulmonary Hypertension: A Rare Case Report.

Eisenmenger syndrome (ES) is considered an absolute contraindication for pregnancy. ES is characterized by a congenital heart abnormality that results in a significant anatomical shunt. Hemodynamic forces generate a left-right shunt, leading to severe pulmonary arterial hypertension (PAH). Eventually, the shunt will become a right-to-left shunt due to increased pulmonary vascular resistance, leading to significant hypoxemia and cyanosis. Pregnant women with ES experience volume overload as a result of the syndrome and the physiological response of pregnancy. The decrease in systemic vascular resistance that occurs during pregnancy also increases the right-to-left shunt, resulting in left ventricular failure. Due to the significant risk to both the mother and the fetus, women are advised to terminate their pregnancy during the first trimester. However, with all the odds, very few cases show positive neonatal and maternal outcomes. Appropriate management of ES includes a multidisciplinary team assembled to monitor and manage the patient carefully and thoroughly. In this paper, we present a case of ES secondary to an atrial septal defect with severe PAH in a 32-year-old woman who underwent a cesarean section at 33 weeks of gestation. She delivered a healthy baby girl. On the seventh postoperative day, she was discharged with no complications.

δ-Tocotrienol feeding modulates gene expression of EIF2, mTOR, protein ubiquitination through multiple-signaling pathways in chronic hepatitis C patients.

BACKGROUND: δ-Tocotrienol is a naturally occurring proteasome inhibitor, which has the capacity to inhibit proliferation and induce apoptosis in several cancer cells obtained from several organs of humans, and other cancer cell lines. Moreover, results of plasma total mRNAs after δ-tocotrienol feeding to hepatitis C patients revealed significant inhibition in the expression of pro-inflammatory cytokines (TNF-α, VCAM1, proteasome subunits) and induction in the expression of ICAM1 and IFN-γ after post-treatment. This down-regulation of proteasome subunits leads to autophagy, apoptosis of immune cells and several genes. The present study describes RNA-sequence analysis of plasma total mRNAs obtained from δ-tocotrienol treatment of hepatitis C patients on gene expression regulated by proteasome. METHODS: Pooled specimens of plasma total mRNAs of pre-dose versus post-dose of δ-tocotrienol treatment of hepatitis C patients were submitted to RNA-sequence analyses. The data based on > 1 and 8-fold expression changes of 2136 genes were uploaded into "Ingenuity Pathway Analyses (IPA)" for core analysis, which describes possible canonical pathways, upstream regulators, diseases and functional metabolic networks. RESULTS: The IPA of "molecules" indicated fold change in gene expression of 953 molecules, which covered several categories of biological biomarkers. Out of these, gene expression of 220 related to present study, 12 were up-regulated, and 208 down-regulated after δ-tocotrienol treatment. The gene expression of transcription regulators (ceramide synthase 3 and Mohawk homeobox) were up-regulated, and gene expression of 208 molecules were down-regulated, involved in several biological functions (HSP90AB1, PSMC3, CYB5R4, NDUFB1, CYP2R1, TNFRF1B, VEGFA, GPR65, PIAS1, SFPQ, GPS2, EIF3F, GTPBP8, EIF4A1, HSPA14, TLR8, TUSSC2). IPA of "causal network" indicated gene regulators (676), in which 76 down-regulated (26 s proteasomes, interleukin cytokines, and PPAR-ligand-PPA-Retinoic acid-RXRα, PPARγ-ligand-PPARγ-Retinoic acid-RARα, IL-21, IL-23) with significant P-values. The IPA of "diseases and functions" regulators (85) were involved with cAMP, STAT2, 26S proteasome, CSF1, IFNγ, LDL, TGFA, and microRNA-155-5p, miR-223, miR-21-5p. The IPA of "upstream analysis" (934) showed 57 up-regulated (mainly 38 microRNAs) and 64 gene regulators were down-regulated (IL-2, IL-5, IL-6, IL-12, IL-13, IL-15, IL-17, IL-18, IL-21, IL-24, IL-27, IL-32), interferon ß-1a, interferon γ, TNF-α, STAT2, NOX1, prostaglandin J2, NF-κB, 1κB, TCF3, and also miRNA-15, miRNA-124, miRNA-218-5P with significant activation of Z-Score (P < 0.05). CONCLUSIONS: This is first report describing RNA-sequence analysis of δ-tocotrienol treated plasma total mRNAs obtained from chronic hepatitis C patients, that acts via multiple-signaling pathways without any side-effects. These studies may lead to development of novel classes of drugs for treatment of chronic hepatitis C patients.

Proteasome inhibitors modulate anticancer and anti-proliferative properties via NF-kB signaling, and ubiquitin-proteasome pathways in cancer cell lines of different organs.

BACKGROUND: Cancer is second most common cause of death in the United State. There are over 100 different types of cancer associated with different human organs, predominantly breast, liver, pancreas, prostate, colon, rectum, lung, and stomach. We have recently reported properties of pro-inflammatory (for treatment of various types of cancers), and anti-inflammatory (for cardiovascular disease and diabetes) compounds. The major problem associated with development of anticancer drugs is their lack of solubility in aqueous solutions and severe side effects in cancer patients. Therefore, the present study was carried out to check anticancer properties of selected compounds, mostly aqueous soluble, in cancer cell lines from different organs. METHODS: The anticancer properties, anti-proliferative, and pro-apoptotic activity of novel naturally occurring or FDA approved, nontoxic, proteasome inhibitors/activators were compared. In addition to that, effect of δ-tocotrienol on expression of proteasome subunits (X, Y, Z, LMP7, LMP2, LMP10), ICAM-1, VCAM-1, and TNF-α using total RNAs derived from plasmas of hepatitis C patients was investigated. RESULTS: Our data demonstrated that following compounds are very effective in inducing apoptosis of cancer cells: Thiostrepton, dexamethasone, 2-methoxyestradiol, δ-tocotrienol, quercetin, amiloride, and quinine sulfate have significant anti-proliferation properties in Hela cells (44% - 87%) with doses of 2.5-20 µM, compared to respective controls. Anti-proliferation properties of thiostrepton, 2-methoxyestradiol, δ-tocotrienol, and quercetin were 70% - 92%. However, thiostrepton, dexamethasone, 2-methoxyestradiol, δ-tocotrienol, quercetin, and quinine sulphate were effective in pancreatic, prostate, breast, lungs, melanoma, Β-lymphocytes, and T-cells (Jurkat: 40% to 95%) compared to respective controls. In lung cancer cells, these compounds were effective between 5 and 40 µM. The IC50 values of anti-proliferation properties of thiostrepton in most of these cell lines were between doses of 2.5-5 µM, dexamethasone 2.5-20 µM, 2-methoxyestradiol 2.5-10 µM, δ-tocotrienol 2.5-20 µM, quercetin 10-40 µM, and (-) Corey lactone 40-80 µM. In hepatitis C patients, δ-tocotrienol treatment resulted in significant decrease in the expression of pro-inflammatory cytokines. CONCLUSIONS: These data demonstrate effectiveness of several natural-occurring compounds with anti-proliferative properties against cancer cells of several organs of humans. Thiostrepton, dexamethasone, 2-methoxyestradiol, δ-tocotrienol and quercetin are very effective for apoptosis of cancer cells in liver, pancreas, prostate, breast, lung, melanoma, Β-lymphocytes and T-cells. The results have provided an opportunity to test these compounds either individually or in combination as dietary supplements in humans for treatment of various types of cancers.

Toxic effects of chromium on tannery workers at Sialkot (Pakistan).

Chromium is widely used in the leather industry, and tannery workers are under constant threat of adverse health effects due to its excessive exposure. Our objective was to find out the toxic effects of chromium on tannery workers at Sialkot, Pakistan. A total of 240 males consisting of 120 workers from tanneries at Sialkot and equal number of controls were included. Blood complete counts, high-sensitive C-reactive protein, malondialdehyde and routine biochemical tests were carried out by routine procedures. Chromium levels in blood (BCr) and urine were analyzed using graphite furnace atomic absorption spectrophotometer Perkin Elmer analyst-200. Results revealed that all the workers were male with average age of 33 years and 15 (13%) had skin rashes, 14 (12%) had chronic bronchitis, 10 (8%) had gastritis and 4 (3%) conjunctivitis. The tannery workers had significantly raised median (interquartile range) of BCr 569 (377-726) nmol/L as compared to 318 (245-397) nmol/L in the control (p < 0.001). Sixty-five (54%) workers had BCr levels above the upper limit set by Agency for Toxic Substance and Drug Registry. The urinary chromium excretion was significantly high in workers 131 (46-312) nmol/L as compared to 13 (3-26) nmol/L in controls (p < 0.01). The workers had hematological, hepatic and renal function impairment because of oxidative stress on body systems. It is concluded that about half of the workers had excessive exposure to chromium in the tanneries at Sialkot. They had significantly raised chromium levels in their biological fluids and adverse health effects due to enhanced oxidative stress and inflammatory changes.