Antiviral drugs in the prophylaxis of HBV infection.

Reactivation of hepatitis B infection (HBV) is known to occur in liver graft recipients and in chronic carriers of the surface antigen of HBV who receive immunosuppressive therapy. The use of hepatitis B immune globulin alone or in combination with antiviral agents such as lamivudine, adefovir, tenofovir, entecavir, famciclovir, ganciclovir, as prophylaxis in HBV liver transplants, has been well documented. In terms of HBV positive carriers undergoing cytotoxic chemotherapy, the preemptive use of nucleoside or nucleotide analogues seems to be effective. Monotherapy or combination of antiviral drugs, as well as the optimal duration of HBV prophylaxis, is to be determined.

Lack of effect of sleep apnea on oxidative stress in obstructive sleep apnea syndrome (OSAS) patients.

PURPOSE: The aim of this study was to evaluate markers of systemic oxidative stress and antioxidant capacity in subjects with and without OSAS in order to investigate the most important factors that determine the oxidant-antioxidant status. METHODS: A total of 66 subjects referred to our Sleep laboratory were examined by full polysomnography. Oxidative stress and antioxidant activity were assessed by measurement of the derivatives of reactive oxygen metabolites (d-ROMs) and the biological antioxidant capacity (BAP) in blood samples taken in the morning after the sleep study. Known risk factors for oxidative stress, such as age, sex, obesity, smoking, hypelipidemia, and hypertension, were investigated as possible confounding factors. RESULTS: 42 patients with OSAS (Apnea-Hypopnea index >15 events/hour) were compared with 24 controls (AHI<5). The levels of d-ROMS were significantly higher (p = 0.005) in the control group but the levels of antioxidant capacity were significantly lower (p = 0.004) in OSAS patients. The most important factors predicting the variance of oxidative stress were obesity, smoking habit, and sex. Parameters of sleep apnea severity were not associated with oxidative stress. Minimal oxygen desaturation and smoking habit were the most important predicting factors of BAP levels. CONCLUSION: Obesity, smoking, and sex are the most important determinants of oxidative stress in OSAS subjects. Sleep apnea might enhance oxidative stress by the reduction of antioxidant capacity of blood due to nocturnal hypoxia.

Ocular side effects of anti-rheumatic medications: what a rheumatologist should know.

Nearly every drug may cause changes to ocular tissues through a variety of mechanisms. Medication overdoses, drug-drug interactions but also chronic administration of medications at the recommended doses may lead to ocular toxicity. The ocular side effects, screening for eye toxicity and treatment guidelines for anti-inflammatory and immunosuppressive drugs commonly used by rheumatologists are reviewed herein.

Antiproliferative activity and induction of apoptosis in human colon cancer cells treated in vitro with constituents of a product derived from Pistacia lentiscus L. var. chia.

In this report, we demonstrate that a 50% ethanol extract of the plant-derived product, Chios mastic gum (CMG), contains compounds which inhibit proliferation and induce death of HCT116 human colon cancer cells in vitro. CMG-treatment induces cell arrest at G(1), detachment of the cells from the substrate, activation of pro-caspases-8, -9 and -3, and causes several morphological changes typical of apoptosis in cell organelles. These events, furthermore, are time- and dose-dependent, but p53- and p21-independent. Apoptosis induction by CMG is not inhibited in HCT116 cell clones expressing high levels of the anti-apoptotic protein, Bcl-2, or dominant-negative FADD, thereby indicating that CMG induces cell death via a yet-to-be identified pathway, unrelated to the death receptor- and mitochondrion-dependent pathways. The findings presented here suggest that CMG (a) induces an anoikis form of cell death in HCT116 colon cancer cells that includes events associated with caspase-dependent pathways; and (b) might be developed into a chemotherapeutic agent for the treatment of human colon and other cancers.

Alpha 2-adrenergic receptors decrease DNA replication and cell proliferation and induce neurite outgrowth in transfected rat pheochromocytoma cells.

Alpha 2-adrenergic receptors (alpha(2)-ARs) have a widespread distribution in the central nervous system (CNS) and affect a number of biochemical and behavioral functions, including stimulation of prefrontal cortex (PFC) and cognitive function. In addition to its role as a classical neurotransmitter, norepinephrine (NE) has been recently shown to exert an important influence on the plasticity in areas of the brain where neurogenesis persists in the adult, notably the subgranular zone (SGZ) within the dentate gyrus of the hippocampus and the olfactory bulb (OB). In regulating adult neurogenesis, the noradrenergic system is functionally integrated with chronic stress and depression. Chronic stress, depression, or depletion of NE in vivo suppress, and antidepressant treatments induce hippocampal neurogenesis by down- or upregulating, respectively, cell proliferation. In the present study we show that alpha(2)-AR subtypes promote the differentiation rather than cell proliferation of PC12 cells. It is conceivable that alpha(2)-ARs might contribute neurotrophic actions in vivo synergistically or in permutation with other neurotrophic factors.

Differential susceptibility to etoposide in clones derived from a human ovarian cancer cell line.

OBJECTIVES: To identify parameters/factors that may contribute to the differential sensitivity to etoposide in two clones isolated from the human ovarian carcinoma SKOV-3 cell line, which does not express p53 and is resistant to platinum-based regimens. METHODS: Differential sensitivity of the cells to etoposide was monitored by microscopy to observe morphological changes, by flow cytometry analyses to detect cell cycle perturbations, and by molecular/biochemical assays to identify events involved in induction of apoptosis. RESULTS: Etoposide treatment (1) induced apoptosis in one clone, ES, but not in another clone, ER, (2) had no effect on the expression of the antiapoptotic proteins Bcl-2 and Bcl-X(L) in both cell clones, whereas the proapoptotic proteins Bak and Bax were dramatically upregulated in ES, but not ER cells, and (3) induced more extensive processing of procaspase-8, procaspase-9, and the caspase-3-targeted substrates, topoisomerase I and PARP, in ES cells. Ectopic overexpression of Bcl-2 in ES cells failed to inhibit etoposide-induced apoptosis. CONCLUSIONS: The differential susceptibility of ES and ER cells to etoposide-induced apoptosis is associated with differences in several events rather than with a specific single genetic regulator of the apoptotic machinery. We propose that the differential response of ovarian cancer patients to etoposide treatment is associated with the number of etoposide-sensitive cells in the tumor.

Ocular manifestations of systemic lupus erythematosus: a clinical review.

Although the eye itself is regarded an 'immune-privileged' organ, systemic lupus erythematosus (SLE) can affect every ocular structure, leading, if left untreated, to significant visual loss or even blindness. Since ocular inflammation in SLE can antedate the diagnosis of the systemic disease and cause significant morbidity, prompt diagnosis and treatment of the underlying systemic autoimmune disease is imperative.

Protective role of oral antioxidant supplementation in ocular surface of diabetic patients.

AIM: To investigate the effect of vitamin C and E supplementation in the levels of nitrite, nitric oxide (NO) related metabolite, and ocular surface parameters in diabetic patients. METHODS: 50 patients with non-insulin dependent diabetes mellitus were given vitamin C (1000 mg/day) and vitamin E (400 IU/day) supplementation for 10 days. Nitrite levels in tears were measured by photometric determination before and after vitamin supplementation. Tear function parameters (Schirmer test I, BUT, ocular ferning test) and brush cytology analysis of the conjunctival epithelium were also evaluated. RESULTS: Nitrite levels were found to be significantly reduced (p<0.05) after 10 days of vitamin C and E supplementation. Improved values for Schirmer test, BUT test, and ocular ferning test were also found. Goblet cell density and grading of squamous metaplasia showed a significant improvement. CONCLUSIONS: Oxidative stress and free radical production are elevated in diabetes mellitus. Antioxidants, such as vitamin C and vitamin E, probably have an important role in reducing the oxidative damage produced by nitric oxide and other free radicals and improving the ocular surface milieu.

Expression of platelet-derived growth factor (PDGF)-related transcripts and synthesis of biologically active PDGF-like proteins by human malignant epithelial cell lines.

Human malignant epithelial cell lines were analyzed for expression of platelet-derived growth factor (PDGF) genes. Of the 12 cell lines tested, 9, derived from breast, lung, gastric, and ovarian carcinomas, were found to express both PDGF-1 and PDGF-2 genes. The levels of both PDGF-1 and PDGF-2 transcripts were superinduced when these cells were treated with cycloheximide, an inhibitor of protein synthesis. These cells also released an activity that in studies with BALB-c/3T3 cells, inhibited binding of 125I-labeled PDGF and stimulated incorporation of [3H]thymidine. This stimulating activity was inhibited after reduction of the conditioned media by mercaptoethanol or after preincubation with antibodies to PDGF. Moreover, this activity was not affected by heat treatment. Immunoprecipitation studies revealed that breast, lung, and gastric carcinoma cells produced PDGF-like proteins that migrated as 30- and 32-kD species under nonreducing conditions and as 15- and 16-kD species under reducing conditions. In contrast, malignant cells of ovarian origin produced 14-16-kD PDGF-like proteins that were unchanged in mobility after reduction. As PDGF receptors were not detected on these malignant epithelial cells, the production of PDGF-like proteins may affect other cells in the microenvironment by paracrine mechanisms and may contribute to excessive cell proliferation, inflammatory reactions, and connective tissue remodeling seen in certain carcinomas.

Constitutive production of platelet-derived growth factor-like proteins by human prostate carcinoma cell lines.

Prostate carcinoma cell lines DU-145 and PC-3 express both platelet derived growth factor (PDGF)-1 and PDGF-2/sis genes. Concomitantly, these cells synthesize and secrete PDGF-like proteins, as judged by indirect immunofluorescence and by direct immunoprecipitation with specific PDGF antiserum. Conditioned media derived from DU-145 and PC-3 cells stimulated the incorporation of [3H]thymidine by 3T3 cells and competed with 125I-labeled PDGF for its binding to cell surface receptors of 3T3 cells. The biological activity was stable to heating at 100 degrees C for 10 min, sensitive to reducing agents, and neutralized by the IgG fraction of PDGF antiserum, properties similar to those of authentic PDGF. Both DU-145 and PC-3 cell lines appear to lack receptors for PDGF as indicated by their inability to mitogenically respond to PDGF and receptor binding of 125I-labeled PDGF. Production of PDGF-like proteins by human prostate carcinoma cells may play an important role in a paracrine mode in the organization of the extracellular matrix of the malignant tissue.

Human iliac artery endothelial cells express both genes encoding the chains of platelet-derived growth factor (PDGF) and synthesize PDGF-like mitogen.

In human umbilical vein and bovine aortic endothelial cells in culture c-sis gene expression and secretion of platelet-derived growth factor (PDGF) has been previously demonstrated. We now report the presence of PDGF-1 and PDGF-2/sis mRNA transcripts in primary cultures of human iliac artery endothelial cells (HIA-EC). Concomitantly, these cells synthesize and secrete PDGF-like proteins identified by direct immunoprecipitation with specific PDGF antiserum. The PDGF proteins secreted by HIA-EC have molecular weights of 31 and 35 kd under nonreducing conditions. Upon reduction these proteins are converted to the monomeric 15- and 16-kd forms. Conditioned media derived from HIA-EC stimulated the incorporation of 3H-thymidine by 3T3 cells and competed with 125I-PDGF for its binding to 3T3 cell membrane receptors. The biologic activity was stable to heating at 100 degrees C for 10 min and sensitive to reducing agents, properties similar to those of authentic PDGF. Production of PDGF-like mitogen by the human arterial endothelial cells may play an important role in the paracrine modulation of arterial wall regeneration following vascular injury.

Metachromasia as the key to aminoglycoside ototoxicity. Preliminary report.

In in-vitro experiments, it was shown that aminoglycosides, in contrast to other antibiotics, inhibited the metachromatic reaction using o-toluidine blue as a basic dye and heparin-Na as a polysulfate-polysaccharide substrate. The inhibitory concentrations were inversely proportional to the free amino groups of aminoglycosides tested. Taking into consideration (a) that the aminoglycosides antagonize the presence of Ca++ and (b) that mechanisms of ototoxicity involve ionic alterations in endolymph, we suggest that: aminoglycoside ototoxicity could be the result of the reaction between aminoglycosides and anionic polyelectrolytes, of the group of polysulfated polysaccharides, in a metachromatic process.

Olfactory involvement in learning processes.

The purpose of this study is to investigate the existing relations between olfaction and acquisition of the two-way conditioned avoidance response (CAR). For this investigation we have used white adult male Wistar rats. Taking into consideration that several structures of the limbic system participate in learning and memory processes and also that olfactory pathway is believed to have connections with the limbic system, we thought it would be interesting to investigate, if peripheral anosmia influences the performance of rats in the two-way avoidance response. It was shown that peripheral anosmia in rats impaired conditioned avoidance response.

Metachromatic reaction and antihistaminic drugs.

We studied the effect of antihistaminic substance on the dye-polysaccharide interaction, using a model in vitro system consisting of heparin-Na and the basic dye o-toluidine blue. The results are recorded on absorption curves in the visible range under standard and modified experimental conditions. We concluded that both histamine and antihistaminic drugs interact in vitro with mucopolysaccharide substances. The results are discussed on a pharmacological basis.