Adenoviral-mediated interferon alpha overcomes resistance to the interferon protein in various cancer types and has marked bystander effects

We have previously shown that intravesical administration of adenovirus encoding human interferon alpha-2b (Ad-IFN) induced a marked regression of superficial human bladder tumors derived from cells that are resistant to over 1 million units/ml of IFNalpha protein in vitro. In addition, Ad-IFN appeared to produce strong bystander effects. In this study, we show that Ad-IFN causes marked inhibition of cell growth and apoptosis in cells of various tumor types, all of which are resistant to IFNalpha protein. In addition, strong perinuclear IFN staining was seen in all cell lines following Ad-IFN transfection and was never observed after exposure to the IFN protein. Ad-IFN induced proteolytic processing of caspases 3, 8 and 9, indicative of enzymatic activation. However, the caspase-8-selective inhibitor, IETDfmk, blocked apoptosis only in the cell lines that were sensitive to the IFNalpha protein and had minimal effect on Ad-IFN-induced caspase-3 or -9 processing and cell death, indicating that death receptor-independent mechanism(s) were involved in the cytotoxic effects observed for cancer cell lines resistant to the IFNalpha protein. Moreover, we document that a yet to be identified soluble factor(s) is responsible for causing the bystander effect observed following Ad-IFN treatment in IFN protein-resistant cancer cells.     

Pathophysiology of atherosclerosis: the role of inflammation

Atherosclerosis is a disease of arteries and is characterized by endothelial dysfunction, vascular inflammation, and the build-up of lipids, cholesterol, calcium, and cellular debris within the intima of the vessel wall. A number of factors commonly characterized as "risk factors" for atherosclerosis have been identified to facilitate the development of atherosclerosis by decreasing NO bioavailability in the vascular endothelium. The serious clinical manifestations of atherosclerosis (including coronary heart disease, stroke, and peripheral vascular disease) augment the need of performing the appropriate diagnostic methods to the patients. The most important diagnostic methods include the usage of biochemical markers and the invasive and non-invasive imaging techniques assessing endothelial function. The main drug categories that have been proved to ameliorate the inflammatory state in atherosclerosis are angiotensin converting enzyme inhibitors/angiotensin receptors blockers, statins, and antioxidants.     

Electrospun fiber mats containing shikonin and derivatives with potential biomedical applications

Alkannin, shikonin (A/S) and their derivatives are naturally occurring hydroxynaphthoquinones with a well-established spectrum of wound healing, antimicrobial, anti-inflammatory, antioxidant and antitumor activity. Clinical studies over the years revealed that A/S derivatives-based wound healing preparations (such as HELIXDERM(?)) are among a very small group of therapeutics that modulate both the inflammatory and proliferative phases of wound healing and present significant tissue regenerative activity. The purpose of the present work was to combine the biological properties of A/S and the advantages of electrospun meshes to prepare a potent topical/transdermal biomaterial for A/S. Four biocompatible polymers (cellulose acetate, poly(L-lactide), poly(lactide-co-glycolide) LA/GA:50/50 and 75/25) were used for the first time, to produce electrospun fiber mats containing either shikonin or A/S mixture in various amounts. Both drugs were effectively loaded into the above biomaterials. The incorporation of drugs did not considerably affect fibers morphology and their mean diameter size varied from 315 to 670 nm. High drug entrapment efficiencies (ranged from 74% to 95%) and appropriate release profiles were achieved, that render these fibers as potential A/S topical/transdermal wound healing dressings. Given the multifunctional activity of the natural products alkannins and shikonins, their consideration as bioactive constituents for tissue engineering scaffolds seems a promising strategy for repairing and regenerating tissues and mainly skin.     

Predictors of HIV Testing and Intention to Test Among Hispanic Farmworkers in South Florida

CONTEXT AND PURPOSE: This study examined the predictors of HIV testing and factors associated with intention to accept a free HIV test among 244 Hispanic migrant/seasonal farmworkers in South Florida. METHODS: Time and space sampling procedures were used to recruit participants in public venues. Bilingual staff interviewed eligible respondents in these settings. FINDINGS: Despite high rates of sexual risk, only 21% of respondents had been tested for HIV. The majority of those tested were females tested during prenatal care. In multivariable logistic regression analyses, being female (odds ratio [OR] = 3.73), having at least 12 years of education (OR = 4.46), earning more than $201 per week (OR = 2.76), and ever having used marijuana (OR = 3.31) were positively associated with having been tested for HIV, while not being documented (OR = 0.24) and having rated one's health as "very good" or "good" (OR = 0.42) were negatively associated with testing. The multivariable predictors of intention to accept a free HIV test were having visited a health care provider and/or an emergency room in the past 12 months (OR = 1.97), having been tested for HIV (OR = 2.36), preferring an HIV test that used a finger stick for specimen collection with results given in 30 minutes (OR = 4.47), and worrying "some" or "a lot" about getting HIV (OR = 3.64). Women (OR = 0.52) were less likely than men to intend to accept a free HIV test. CONCLUSIONS: Our findings highlight the importance of routinely offering HIV testing to sexually active individuals in high HIV prevalence areas. They also suggest the need to make testing more accessible to migrant and seasonal farmworkers.     

Inhibitory activity of minor polyphenolic and nonpolyphenolic constituents of olive oil against in vitro low-density lipoprotein oxidation

The minor polyphenolic and nonpolyphenolic constituents of olive oil were examined, in various doses, against copper ion-induced low-density lipoprotein (LDL) oxidation and were found, in optimal doses (final concentration, 10 microM or 20 microM), to have remarkable biological activity, contributing to that previously reported for the major phenolic compounds. The main phytosterols, beta-sitosterol, campesterol, and stigmasterol, were found to have 43.8%, 37.3%, and 33.4% LDL mean protection (MP) activity, respectively, while free cholesterol exhibited 43.2% MP. The triterpenoid derivative compounds, ursolic acid, uvaol, and oleanolic acid, had similar MP activities of 50.5%, 46.8%, and 46.0%, respectively. Tocopherol (Toc) isomers exhibited an increasing effect in the following order: alpha-Toc (33.6%) < beta-Toc (36.1%) < gamma-Toc (42.9%) < delta-Toc (46.0%). The flavonoid polyphenols, quercetin, luteolin, and rutin, exhibited the highest activities--46.8%, 49.5%, and 53.7% MP, respectively, comparable to the 49.0% MP activity found for oleuropein. These findings indicate the relative independence of LDL protection activity in regard to structural differences among the involved compounds. A relation to the Mediterranean diet is also demonstrated.     

Comparative study of sister chromatid exchange induction and antitumor effects by homo-aza-steroidal esters of [p-[bis(2-chloroethyl)amino]phenyl]butyric acid

The present work was undertaken in order to test the hypothesis that the Sister Chromatid Exchange (SCE) assay in vitro can be used for the prediction of in vivo tumor response to newly synthesized potential chemotherapeutics. The effect of three homo-aza-steroidal esters containing the -CONH- in the steroidal nucleus, 1, 2, and 3 on SCE rates and on cell kinetics in cultured human lymphocytes was studied. The antitumor activity of these compounds was tested on leukemia P388- and leukemia L1210-bearing mice. The three substances induced statistically significant enhancement of SCEs and of cell division delays. Compounds 1 and 3 were identified, on a molar basis, as more effective inducers of SCEs and of cell division delays compared with compound 2. Compounds 1 and 3 had upon both experimental tumors better therapeutic effects compared with compound 2 at equitoxic doses. Therefore, the order of the antitumor effectiveness of the three compounds coincided with the order of the cytogenetic effects they induced.     

Erythromycin accelerates delayed gastric emptying of solids in patients after truncal vagotomy and pyloroplasty.

OBJECTIVE--To find out if erythromycin (a motilin agonist) accelerated gastric emptying after vagotomy and in normal subjects. DESIGN--Double blind controlled study. SETTING--Two referral centres. SUBJECTS--15 patients who had previously undergone vagotomy and who did (n = 8) or did not (n = 7) have symptoms of gastric stasis and 10 normal controls. INTERVENTIONS--A standard meal containing 185 x 10(5) Bq -99mTc was eaten after either erythromycin 200 mg or 40 ml placebo (normal saline) had been given intravenously. Subjects were then scanned by gamma camera. MAIN OUTCOME MEASURES--Measurement of: the length of time from completion of the meal to the onset of gastric emptying; the length of time from completion of the meal until half of the meal had left the stomach; the length of the time from the onset of gastric emptying until half of the meal had left the stomach; and the percentage of the meal that was left in the stomach at 60 and 120 min after the end of the meal. RESULTS--Gastric emptying was significantly delayed in those patients with symptoms compared with normal subjects and patients without symptoms. Erythromycin accelerated the first two phases of gastric emptying in all patients and normal subjects, but did not affect the length of time from the onset of gastric emptying until half the meal had left the stomach. CONCLUSION--Erythromycin could be a useful gastrokinetic agent in patients with symptoms of gastric stasis after vagotomy.     

Blood profile holds clues to role of infection in a premonitory state for idiopathic parkinsonism and of gastrointestinal infection in established disease

The two-stage neuroinflammatory process, containment and progression, proposed to underlie neurodegeneration may predicate on systemic inflammation arising from the gastrointestinal tract. Helicobacter infection has been described as one switch in the pathogenic-circuitry of idiopathic parkinsonism (IP): eradication modifies disease progression and marked deterioration accompanies eradication-failure. Moreover, serum Helicobacter-antibody-profile predicts presence, severity and progression of IP. Slow gastrointestinal-transit precedes IP-diagnosis and becomes increasingly-apparent after, predisposing to small-intestinal bacterial-overgrowth (SIBO). Although IP is well-described as a systemic illness with a long prodrome, there has been no comprehensive overview of the blood profile. Here, it is examined in relation to Helicobacter status and lactulose-hydrogen-breath-testing for SIBO. A robust finding of reduced lymphocyte count in 126 IP-probands and 79 spouses (without clinically-definite IP), compared with that in 381 controls (p < 0.001 in each case), was not explained by Helicobacter-status or breath-hydrogen. This complements a previous report that spouses were 'down-the-pathway' to 'clinically-definite' disease. In 205 other controls without clinically-definite IP, there were strong associations between sporadic cardinal features and immunoglobulin class concentration, not explained by Helicobacter-status. Premonitory states for idiopathic parkinsonism associated with relative lymphopenia, higher serum immunoglobulin concentrations and evidence of enteric-nervous-system damage may prove viral in origin. Although only 8% of the above 79 spouses were urea-breath-test-positive for Helicobacter, all 8 spouses with clinically-definite IP were (p < 0.0001). Transmission of a 'primer' to a Helicobacter-colonised recipient might result in progression to the diagnostic threshold. Twenty-five percent of the 126 probands were seropositive for anti-nuclear autoantibody. In 20 probands, monitored before and serially after anti-Helicobacter therapy, seropositivity marked a severe hypokinetic response (p = 0.03). It may alert to continuing infection, even at low-density. Hyperhomocysteinemia is a risk factor for dementia and depression. Serum homocysteine exceeded the target in 43% of the 126 IP-probands. It was partially explained by serum B12 (12% variance, p < 0.001), but not by Helicobacter-status (gastric-atrophy uncommon in IP) or levodopa treatment. Immune-inflammatory activation increases homocysteine production. Since an estimated 60% of probands are hydrogen-breath-test positive, SIBO, with its increased bacterial utilisation of B12, is a likely cause. Thus, two prognostic indicators in established IP fit with involvement of Helicobacter and SIBO.