Interleukin-12 induces a Th1-like response to Burkholderia mallei and limited protection in BALB/c mice

We evaluated the effect of interleukin (IL)-12 on the immune response to Burkholderia mallei in BALB/c mice. Mice were vaccinated with non-viable B. mallei cells with or without IL-12. There was a seven- to nine-fold increase in IgG2a levels, and a significant increase in the proliferative response and interferon (IFN)-gamma production by splenocytes from mice that received B. mallei and IL-12. We saw an increase in survivors in the groups of mice that received B. mallei and IL-12 when challenged, compared to mice that received only B. mallei or IL-12. The results suggest that IL-12 can enhance the Th1-like immune response to B. mallei and mediate limited protection from a lethal challenge.     

The evidence for efficacy of omega-3 fatty acids in preventing or slowing the progression of retinitis pigmentosa: a systematic review

BACKGROUND: Studies in preterm and term human infants have suggested that a dietary supply of omega-3 fatty acids is essential for optimal visual development. Several basic science studies support the hypothesis that omega-3 fatty acids may be useful therapeutic agents for pathologies of the retina and lens. As part of a systematic review of the effect of omega-3 fatty acids on eye health, the purpose of this study was to conduct a systematic review of the scientific-medical literature to appraise and synthesize the evidence for the effects of omega-3 fatty acids in preventing the development or progression of retinitis pigmentosa. METHODS: A comprehensive search was undertaken in MEDLINE, PREMEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Global Health, and Dissertation Abstracts. Unpublished literature was sought through manual searches of reference lists of included studies and key review articles and from the files of content experts. Searches were not restricted by language of publication, publication type, or study design. Eligibility criteria were applied to screen eligible studies on two levels. Data extraction and quality assessment were performed. RESULTS: Six studies published between 1995 and 2004 met eligibility criteria in investigating the question of the possible value of omega-3 fatty acids in slowing the progression of retinitis pigmentosa. Meta-analysis was not performed because there was not enough available information for formal quantitative analysis. INTERPRETATION: There are trends in improvement of some retinitis pigmentosa outcomes with omega-3 fatty acids in the higher quality studies. Clinical research is preliminary in this field, however. Accordingly, definitive answers will require significantly more observational and interventional clinical research.     

Different death stimuli evoke apoptosis via multiple pathways in retinal pigment epithelial cells

Loss of retinal pigment epithelial (RPE) cells via apoptosis plays a prominent role in several retinal degenerative diseases, such as age-related macular degeneration, and with light damage. Strategies for preservation of vision that would interrupt the apoptotic cascade require understanding the molecular events associated with apoptosis. This study investigated the susceptibility of RPE to caspase-dependent and -independent apoptotic pathways when challenged with different stimuli, including oxidants, anti-Fas antibody, and activated cytotoxic T lymphocytes (CTLs). These experiments used novel RPE cell lines developed from wildtype and heterozygous mice with reduced levels of either Mn superoxide dismutatse (SOD) or CuZnSOD. Peroxide and 4-hydroxynonenal induced apoptosis through both caspase-independent and -dependent pathways, respectively. With both oxidants, translocation of apoptosis inducing factor into the nucleus was observed. Cells containing reduced levels of CuZnSOD were the most susceptible to oxidant-induced cell death. Targeted killing by CTLs and activation of the Fas death receptor induced caspase-dependent apoptosis. These results show stimulus-specific activation of either the caspase-dependent or -independent pathway. Since cultured RPE express the protein components required for different apoptotic pathways, they provide a good model system for studying molecular events associated with multiple signals that lead to cell death.     

Maculopathy due to the R345W substitution in fibulin-3: distinct clinical features, disease variability, and extent of retinal dysfunction

PURPOSE: To determine (1) clinical features that distinguish maculopathy due to the R345W substitution in fibulin-3 from other forms of inherited or early-onset drusen, (2) the phenotypic variability, and (3) the extent of retinal disease in those with a positive molecular diagnosis. METHODS: Affected individuals underwent ophthalmic examination, digital color fundus photography, fundus autofluorescence (AF) imaging, and psychophysical testing with automated photopic and dark-adapted perimetry and fine matrix mapping. Blood samples were taken for DNA extraction and screening for the R345W mutation in fibulin-3. Patients were subsequently divided into mutation-positive and -negative groups, to compare the identified phenotypic findings in these two sets of subjects. RESULTS: Twenty-nine subjects from 19 families were ascertained with inherited or early-onset drusen. Twenty-four (83%) subjects from 15 families were found to harbor the R345W fibulin-3 mutation. Peripapillary deposition and a radial distribution of macular drusen were consistent, distinguishing signs in the mutation-positive group. Subretinal neovascular membrane (SRNVM) was a rare occurrence, affecting only 1 of 48 eyes, whereas hyperpigmentation and atrophy of the retinal pigment epithelium (RPE) were common in older mutation-positive patients. Increased AF corresponding to the drusen was detected in both the mutation-positive and -negative groups. The phenotype in the group of patients positive for the R345W mutation was extremely variable, with evidence of interocular, intrafamilial, and interfamilial variability in visual loss, natural history, ophthalmoscopic findings, autofluorescence imaging, and psychophysical data. The novel finding of nonpenetrance was observed in a 62-year-old asymptomatic, mutation-positive man. The findings from detailed perimetry performed on a subset of subjects were consistent with the presence of widespread retinal dysfunction not isolated to the macula. CONCLUSIONS: Marked inter- and intrafamilial variation associated with the fibulin-3 R345W mutation in terms of retinal appearance, severity, progression, and nonpenetrance were identified. It was noted that SRNVM is a rare occurrence in R345W fibulin-3 maculopathy. These findings are helpful for advice regarding prognosis and for genetic counseling. The findings established that the presence of peripapillary deposit is highly likely to indicate that a patient carries the R345W mutation.     

Modulation of cutaneous wound healing by ozone: differences between young and aged mice

Cutaneous tissues are frequently exposed to prooxidative environments, including UV radiation and air pollutants. Among the latter, ozone (O(3)) is of particular concern because of its high and dominating presence in photochemical smog. It is well known that O(3) depletes small molecular weight antioxidants, oxidizes proteins, induces lipid peroxidation and activates cellular responses in various tissues. Using an in vivo model (SKH-1 hairless mice), the interaction between O(3) exposure (0.5ppmx6h/day) and age was examined in relation to cutaneous wound healing. Compared to younger (8 weeks) mice, older (18 months) mice exposed to O(3) (day 0 to day 9 after wounding) exhibited delayed wound closure, increased lipid peroxidation (measured as 4-HNE protein adducts) and protein oxidation (measured as carbonyls concentration) and decreased levels of P-IkappaBalpha and TGFbeta protein. These findings support the hypothesis that oxidant pollutant exposure and age interact so as to disrupt normal wound healing processes.     

Hyrtiazepine, an azepino-indole-type alkaloid from the Red Sea marine sponge Hyrtios erectus

Biological and chemical investigations of the methanolic crude extract of the Red Sea marine sponge Hyrtios erectus led to the isolation of a novel azepino-indole-type alkaloid named hyrtiazepine (2) and 5-hydroxy-1H-indole-3-carboxylic acid methyl ester (3), together with the known metabolites hyrtiosulawesine (1), 5-hydroxyindole-3-carbaldehyde (4), hyrtiosin A (5), and hyrtiosin B (6). Their structures were elucidated on the basis of mass spectrometry and detailed 2D NMR spectroscopic data. Hyrtiosulawesine (1) displayed a significant antiphospholipase A2 activity with an IC50 value of 14 microM in a fluorometric assay using Crotalus adamanteus venom phospholipase A2.     

Phenolic glycosides with antioxidant activity from the stem bark of Populus davidiana

Phytochemical study on the EtOAc-soluble fraction of the stem bark of Populus davidiana resulted in the isolation of 10 phenolic glycosides (1-10), which were identified on the basis of physicochemical and spectroscopic analyses. Among these, three new compounds, populosides A-C (1-3), were determined to be 2-coumaroylmethyl-4-hydroxyphenyl-beta-D-glucopyranoside, 2-coumaroylmethylphenyl-beta-D-glucopyranoside, and 2-feruoylmethylphenyl-beta-D-glucopyranoside, respectively. Compounds 1-10 were tested for their radical scavenging activity against an azo radical, ABTS*+. Of these, populosides A-C (1-3), populoside (4), grandidentatin (8), salireposide (9), and coumaroyl-beta-D-glucoside (10) exhibited antioxidant activity in this assay.     

Regulation of E-cadherin expression by VHL and hypoxia-inducible factor

Mutations in von Hippel-Lindau tumor suppressor gene (VHL) underlie the VHL hereditary cancer syndrome and also occur in most sporadic clear cell renal cell cancers (CCRCC). Currently, the mechanism(s) by which VHL loss of function promotes tumor development in the kidney are not fully elucidated. Here, we show that VHL inactivation in precancerous lesions in kidneys from patients with VHL disease correlates with marked down-regulation of the intercellular adhesion molecule E-cadherin. Moreover, in VHL-defective cell lines (RCC4 and RCC10) derived from sporadic CCRCC, reexpression of VHL was found to restore E-cadherin expression. The product of the VHL gene has multiple reported functions, the best characterized of which is its role as the recognition component of an ubiquitin E3 ligase complex responsible for mediating oxygen-dependent destruction of hypoxia-inducible factor-alpha (HIF-alpha) subunits. We show that HIF activation is necessary and sufficient to suppress E-cadherin in renal cancer cells. Given the fundamental role of E-cadherin in controlling epithelial behavior, our findings give insight into how VHL inactivation/HIF activation may lead to kidney cancer and also indicate a mechanism by which reduced oxygenation could alter E-cadherin expression in other cancers and influence normal homeostasis in other epithelia.     

Neoadjuvant concurrent chemoradiation with weekly paclitaxel and carboplatin for patients with oesophageal cancer: a phase II study

This study was performed to assess the efficacy and safety of preoperative chemoradiation consisting of carboplatin and paclitaxel and concurrent radiotherapy for patients with resectable (T2-3N0-1M0) oesophageal cancer. Treatment consisted of paclitaxel 50 mg m(-2) and carboplatin AUC=2 on days 1, 8, 15, 22 and 29 and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week), followed by oesophagectomy. All 54 entered patients completed the chemoradiation without delay or dose-reduction. Grade 3-4 toxicities were: neutropaenia 15%, thrombocytopaenia 2%, and oesophagitis 7.5%. After completion of the chemoradiotherapy 63% had a major endoscopical response. Fifty-two patients (96%) underwent a resection. The postoperative mortality rate was 7.7%. All patients had an R0-resection. The pathological complete response rate was 25%, and an additional 36.5% had less than 10% vital residual tumour cells. At a median follow-up of 23.2 months, the median survival time has not yet been reached. The probability of disease-free survival after 30 months was 60%. In conclusion, weekly neoadjuvant paclitaxel and carboplatin with concurrent radiotherapy is a very tolerable regimen and can be given on an outpatient basis. It achieves considerable down staging and a subsequent 100% radical resection rate in this series. A phase III trial with this regimen is now ongoing.