Hypogonadism and sexual dysfunction in male cancer survivors receiving chronic opioid therapy

The purpose of this study was to determine the prevalence of central hypogonadism and sexual dysfunction in male cancer survivors exposed to chronic high-dose oral opioid therapy. We studied 20 male patients with cancer-related chronic pain who were disease-free for at least one year. All patients consumed at least 200 mg-equivalent of morphine on a daily basis for at least one year. Participants completed the Sexual Desire Inventory questionnaire and serum levels of testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were assessed. Serum testosterone levels were reduced in these patients. The median value was 140 ng/dL (normal 241-827). There was no compensatory increase in FSH and LH. The median FSH level was 3.5 mIU/mL (normal 1.4-18.1). The median LH level was 2.1 mIU/mL (normal 1.5-9.3). The mean dyadic sexual desire score was 23.9+/-15.7 (normal value, 42.8+/-8.9). The mean solitary sexual desire score was 1.3+/-1.9 (normal value, 10.6+/-1.9). Our data suggest that chronic exposure to high-dose oral opioid therapy may result in marked central hypogonadism and sexual dysfunction. Given the increasing use of long-term opioid therapy for chronic pain syndromes, further investigation into these findings is warranted.     

The tumor suppressor activity of MDA-7/IL-24 is mediated by intracellular protein expression in NSCLC cells.

mda-7/IL-24 (HGMW-approved symbol IL24) is a tumor suppressor gene whose expression is lost during tumor progression. Gene transfer using adenoviral mda-7/IL-24 (Ad-mda7) exhibits minimal toxicity on normal cells while inducing potent apoptosis in a variety of cancer cell lines. Ad-mda7-transduced cells express high levels of MDA-7 protein intracellularly and also secrete a soluble form of MDA-7 protein. In this study, we sought to determine whether the intracellular or secreted MDA-7 protein was responsible for anti-tumor activity in H1299 lung tumor cells. Ad-mda7 transduction of lung tumor cells increased expression of stress-related proteins, including BiP, GADD34, PP2A, caspases 7 and 12, and XBP-1, consistent with activation of the UPR pathway, a key sensor of endoplasmic reticulum (ER)-mediated stress. Blocking secretion of MDA-7 did not inhibit apoptosis, demonstrating that intracellular MDA-7 was responsible for cytotoxicity. Consistent with this result, when applied directly to lung cancer cells, soluble MDA-7 protein exhibited minimal cytotoxic effect. We then generated mda-7 expression constructs using vectors that target the expressed protein to various subcellular compartments, including cytoplasm, nucleus, and ER. Only full-length and ER-targeted MDA-7 elicited cell death in tumor cells. Thus in lung cancer cells, Ad-mda7 activates the UPR stress pathway and induces apoptosis via intracellular MDA-7 expression in the secretory pathway.     

Relation of myocardial perfusion to mortality after primary percutaneous coronary intervention

In patients who undergo primary percutaneous coronary intervention (PCI), poor post-PCI myocardial blush is associated with increased mortality, even when epicardial perfusion is adequate. This observation has important implications for the methods of evaluating primary PCI results and the strategies used to improve myocardial reperfusion.     

Antifungal Saponins from the Maya Medicinal Plant Cestrum schlechtendahlii G. Don (Solanaceae)

Bioassay‐guided fractionation of the crude extract (80% EtOH) of the leaves of Cestrum schlechtendahlii, a plant used by Q'eqchi' Maya healers for treatment of athlete's foot, resulted in the isolation and identification of two spirostanol saponins (1 and 2). Structure elucidation by MS, 1D‐NMR, and 2D‐NMR spectroscopic methods identified them to be the known saponin (25R)‐1β,2α‐dihydroxy‐5α‐spirostan‐3‐β‐yl‐O‐α‐l ‐rhamnopyranosyl‐(1 → 2)‐β‐d ‐galactopyranoside (1) and new saponin (25R)‐1β,2α‐dihydroxy‐5α‐spirostan‐3‐β‐yl‐O‐β‐d ‐galactopyranoside (2). While 2 showed little or no antifungal activity at the highest concentration tested, 1 inhibited growth of Saccharomyces cerevisiae (minimum inhibitory concentration (MIC) of 15–25 μM), Candida albicans, Cryptococcus neoformans, and Fusarium graminearum (MIC of 132–198 μM). Copyright © 2015 John Wiley & Sons, Ltd.     

Arsenic-induced alteration in intracellular calcium homeostasis induces head kidney macrophage apoptosis involving the activation of calpain-2 and ERK in Clarias batrachus

We had earlier shown that exposure to arsenic (0.50 μM) caused caspase-3 mediated head kidney macrophage (HKM) apoptosis involving the p38-JNK pathway in Clarias batrachus. Here we examined the roles of calcium (Ca²⁺) and extra-cellular signal-regulated protein kinase (ERK), the other member of MAPK-pathway on arsenic-induced HKM apoptosis. Arsenic-induced HKM apoptosis involved increased expression of ERK and calpain-2. Nifedipine, verapamil and EGTA pre-treatment inhibited the activation of calpain-2, ERK and reduced arsenic-induced HKM apoptosis as evidenced from reduced caspase-3 activity, Annexin V-FITC-propidium iodide and Hoechst 33342 staining. Pre-incubation with ERK inhibitor U 0126 inhibited the activation of calpain-2 and interfered with arsenic-induced HKM apoptosis. Additionally, pre-incubation with calpain-2 inhibitor also interfered with the activation of ERK and inhibited arsenic-induced HKM apoptosis. The NADPH oxidase inhibitor apocynin and diphenyleneiodonium chloride also inhibited ERK activation indicating activation of ERK in arsenic-exposed HKM also depends on signals from NADPH oxidase pathway. Our study demonstrates the critical role of Ca²⁺ homeostasis on arsenic-induced HKM apoptosis. We suggest that arsenic-induced alteration in intracellular Ca²⁺ levels initiates pro-apoptotic ERK and calpain-2; the two pathways influence each other positively and induce caspase-3 mediated HKM apoptosis. Besides, our study also indicates the role of ROS in the activation of ERK pathway in arsenic-induced HKM apoptosis in C. batrachus.     

MDA-7/IL-24 is a unique cytokine--tumor suppressor in the IL-10 family

The melanoma differentiation associated gene-7 (mda-7) cDNA was isolated by virtue of being induced during melanoma differentiation. Initial gene transfer studies convincingly demonstrated potent antitumor effects of mda-7. Further studies showed that the mechanism of antitumor activity was due to induction of apoptosis. Most striking was the tumor-selective killing by mda-7 gene transfer--normal cells were unaffected by Adenoviral delivery of mda-7 (Ad-mda7). A variety of molecules implicated in apoptosis and intracellular signaling are regulated by Ad-mda7 transduction. Different apoptosis effector proteins are regulated in different tumor types, suggesting that Ad-mda7 may regulate various signaling pathways. mda-7 encodes a secreted protein, MDA-7, which has now been designated as IL-24, and is a novel member of the IL-10 cytokine family. MDA-7/IL-24 protein is actively secreted from cells after mda-7 gene transfer. In human peripheral blood mononuclear cells (PBMC), STAT3 activation by MDA-7/IL-24 is followed by elaboration of secondary Th1 cytokines, demonstrating that MDA-7/IL-24 is a pro-Th1 cytokine. Furthermore, MDA-7/IL-24 is antagonized by the prototypic Th2 cytokine IL-10. MDA-7/IL-24 protein is endogenously expressed in cultured NK and B-cells and is also expressed in dendritic cells in tissues. MDA-7/IL-24 protein is expressed in nevi and melanoma primary tumors, to varying degrees, but is rarely expressed in malignant melanoma or other human tumors evaluated. Indeed, loss of MDA-7/IL-24 protein expression correlates strongly with melanoma tumor invasion and disease progression. The "bystander" effects proposed for MDA-7/IL-24 protein include immune stimulation, antiangiogenesis and receptor-mediated cytotoxicity. Thus, mda-7 is a unique multifunctional cytokine in the IL-10 family and may have potent antitumor utility in a clinical setting.     

Limbal autografting: comparison of results in the acute and chronic phases of ocular surface burns

PURPOSE: To compare outcomes of limbal autograft transplantation (LAT) in the acute and chronic phases of ocular surface burns. METHODS: Retrospective analysis of case records of 16 consecutive patients who underwent LAT for ocular surface burns, at our institute, between April 1994 and March 1997. RESULTS: Limbal autograft transplantation was successful in reconstructing the corneal surface and restoring ocular comfort in 15 (93.8%) eyes. Limbal autografting failed to reconstruct the ocular surface in one patient undergoing surgery 2 weeks after grade IV alkali burns. In 13 eyes with counting fingers or worse vision, functional success (visual acuity >20/400) was attained after LAT in nine (69.2%) eyes. Visual acuity > or = 20/80 was achieved in two (25%) of eight eyes undergoing surgery for a persistent epithelial defect (PED) and five of six (83.3%) eyes undergoing surgery after the epithelial defect had healed (p = 0.03). Nine patients underwent simultaneous superior and inferior limbal autografting. Mean epithelial healing time in six of these patients undergoing surgery in the acute phase of injury (<4 months) was 15+/-6.1 days. In three patients undergoing a similar procedure in the chronic phase of injury, the healing time was 8.3+/-6.7 days. CONCLUSIONS: Limbal autograft transplantation is successful in reconstructing the corneal surface and restoring ocular comfort after ocular surface burns. Surgery in the acute phase of injury (<4 months), in the presence of a PED, could result in delayed corneal reepithelialization and poorer visual prognosis. If performed in the acute phase of injury, LAT should be performed after adequate limbal vascularization and resolution of surface inflammation in the recipient eye, avoiding graft placement over ischemic limbus.