Specific targeting and noninvasive magnetic resonance imaging of an asthma biomarker in the lung using polyethylene glycol functionalized magnetic nanocarriers

Simultaneous inhibition of IL4 and IL13 via the common receptor chain IL4Rα to block adequately their biologic effects presents a promising therapeutic approach to give the additional relief required for asthma patients. In this study, superparamagnetic iron oxide nanoparticles were conjugated with anti‐IL4Rα blocking antibodies via polyethylene glycol (PEG) polymers. The delivery of these blocking antibodies to the inflammatory sites in the lung via the developed nanocarriers was assessed using noninvasive free‐breathing pulmonary MRI. Biocompatibility assays confirmed the safety of the developed nanocarriers for pre‐clinical investigations. For all the investigated formulations, nanocarriers were found to be very stable at neutral pH. However, the stability noticeably decreased with the PEG length in acidic environment and thus the loaded antibodies were preferentially released. Immunofluorescence and fluorimetry assays confirmed the binding of the nanocarriers to the IL4Rα asthma biomarker. Pulmonary MRI performed using an ultra‐short echo time sequence allowed simultaneous noninvasive monitoring of inflammatory responses induced by ovalbumin challenge and tracking of the developed nanocarriers, which were found to colocalize with the inflammatory sites in the lung. Targeting of the developed nanocarriers to areas rich in IL4Rα positive inflammatory cells was confirmed using histological and flow cytometry analyses. The anti‐IL4Rα‐conjugated nanocarriers developed here have been confirmed to be efficient in targeting key inflammatory cells during chronic lung inflammation following intrapulmonary administration. Targeting efficiency was monitored using noninvasive MRI, allowing detection of the nanocarriers’ colocalizations with the inflammatory sites in the lung of ovalbumin‐challenged asthmatic mice. Copyright © 2015 John Wiley & Sons, Ltd.     

The Bath Ankylosing Spondylitis Activity and Function Indices (BASDAI and BASFI) and their correlation with main symptoms experienced by patients with spondyloarthritis

With the aim of assessing whether the Bath Ankylosing Spondylitis Activity and Function Indices (BASDAI and BASFI) are reliable measures of disease activity and function in patients with spondyloarthritides (SpAs), 341 patients with SpA (representing ankylosing spondylitis (14.5%), psoriatic arthritis (27.3%), enteropathic arthritis (6.3%), reactive arthritis (4.9%), and undifferentiated arthritis (46.5%) were asked to complete the BASDAI and BASFI. They were asked to report what their main problems associated with the disease were from a list of seven symptoms: fatigue, neck pain, upper back pain, lower back pain, stiffness, joint pain or swelling, and pain with pressure on joints. Correlations between the main symptoms experienced by patients with SpAs and the indices, defined by Spearman’s correlation coefficient, showed that BASDAI best correlated with neck pain [BASDAI 2 and total BASDAI score correlate strongly (p = 0.003 and 0.001, respectively), and BASDAI 1, 4, and 5 correlate moderately (p = 0.03, 0.02, and 0.01, respectively)], followed by stiffness, upper back pain, pain with pressure, lower back pain, fatigue, and joint pain. Stiffness correlated strongly with nine of ten items on BASFI (BASFI 1 showed moderate correlation, p = 0.01), followed by upper back pain (four of ten items correlated strongly, three of ten correlated moderately), neck pain (three of ten tasks correlated strongly and four of ten correlated moderately), lower back pain (one task correlated strongly, five moderately), joint pain and swelling (four tasks correlated moderately), fatigue (three tasks correlated moderately), and pain with pressure (two tasks correlated moderately). BASDAI and BASFI only partly reflect disease activity and patients’ functional capacity in SpAs. An alternate instrument is required to assess SpA disease activity and functional capacity more precisely.     

Maternal sociodemographic characteristics and risk factors of antepartum fetal death

The objectives of this study were to assess the sociodemographic profile and to identify the risk factors of ante-partum fetal death which occurs after the age of viability of fetus. This prospective observational study was conducted in the Obstetrics department of Ad-din Women Medical College Hospital during the period of June, 2009 to July, 2010. A total of 14,015 pregnant patients were admitted in the study place after the age of viability, which was taken as 28 weeks of gestation for our facilities. Eighty-three (0.59%) of them were identified as intrauterine fetal death. Assessment of maternal sociodemographic characteristics and maternal-fetal risk factors were evaluated with a semi structured questionnaire pretested. Majority (81.92%, n=68) of the patients were below 30 years of age, 78.31% belonged to middle socioeconomic group. Almost 58% women had education below SSC level and 28.91% took regular antenatal checkup. About 61.45% patients were multigravida. Most (59.04%) ante-partum deaths were identified below 32 weeks of pregnancy. Out of 83 patients, maternal risk factors were identified in 41(49.59%) cases where fetal risk factors were found in 16(19.27%) cases; no risk factors could be determined in rests. Hypertension (48.78%), diabetes (21.95%), hyperpyrexia (17.3%), abruptio placentae (4.88%) and UTI (7.36%) were identified as maternal factors; and congenital anomaly (37.5%), Rh incompatibility (37.5%), multiple pregnancy (12.5%) and post-maturity (12.5%) were the fetal risk factors. Here, proximal biological risk factors are most important in ante-partum fetal deaths. More investigations and facilities are needed to explain the causes of antepartum deaths.     

Oxidative stress and toxicity induced by the nucleoside reverse transcriptase inhibitor (NRTI)--2',3'-dideoxycytidine (ddC): relevance to HIV-dementia

Human immunodeficiency virus dementia (HIVD) is the most common form of dementia occurring among young adults. In HIVD, neuronal cell loss occurs in the absence of neuronal infection. With the advent of highly active anti-retroviral therapy (HAART), the incidence of HIVD has drastically reduced, though prevalence of milder forms of HIVD continues to rise. Though these agents have been used successfully in suppressing viral production, they have also been associated with a number of side effects. Here we examine the possible role of NRTIs, in particular 2',3'-dideoxycytidine (ddC), in the neuropathology of HIVD. Synaptosomes and isolated mitochondria treated and incubated for 6 h with CSF-achievable concentrations of ddC, i.e., 6-11 ng/ml, were found to show a significant increase in oxidative stress with 40 nM ddC as measured by protein carbonyls and 3-nitrotyrosine (3NT), effects that were not observed in the more tolerable NRTI, 3TC. Protection against protein oxidation induced by ddC was observed when brain mitochondria were isolated from gerbils 1 h after injection i.p. with the brain accessible antioxidant and glutathione mimetic, tricyclodecan-9-yl-xanthogenate (D609). In addition, there is a significant reduction in the levels of anti-apoptotic protein Bcl-2 and a significant increase in cytochrome c release and also a significant increase in the expression of pro-apoptotic protein caspase-3 after mitochondria were treated with 40 nM ddC. The results reported here show that ddC at 40 nM can induce oxidative stress, cause the release of cytochrome c, and in addition, reduce the levels of anti-apoptotic proteins, increase the levels of pro-apoptotic proteins, thereby increasing the possibility for induction of apoptosis. These findings are consistent with the notion of a possible role of the NRTIs, and in particular, ddC, in the mechanisms involved in HIVD.     

An increase in S-glutathionylated proteins in the Alzheimer's disease inferior parietal lobule, a proteomics approach

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neurofibrillary tangles, senile plaques, and loss of synapses. Many studies support the notion that oxidative stress plays an important role in AD pathogenesis. Previous studies from our laboratory employed redox proteomics to identify oxidatively modified proteins in the AD inferior parietal lobule (IPL) and hippocampus. The proteins were consistent with biochemical or pathological alterations in AD and have been central to further investigations of the disease. The present study focused on the identification of specific targets of protein S-glutathionylation in AD and control IPL by using a redox proteomics approach. For AD IPL, we identified deoxyhemoglobin, alpha-crystallin B, glyceraldehyde phosphate dehydrogenase (GAPDH), and alpha-enolase as significantly S-glutathionylated relative to these brain proteins in control IPL. GAPDH and alpha-enolase were also shown to have reduced activity in the AD IPL. This study demonstrates that specific proteins are sensitive to S-glutathionylation, which most likely is due to their sensitivity to cysteine oxidation initiated by the increase in oxidative stress in the AD brain.     

Redox proteomics identification of oxidatively modified brain proteins in Alzheimer's disease and mild cognitive impairment: insights into the progression of this dementing disorder

Alzheimer disease is a common age-related neurodegenerative disease characterized pathologically by senile plaques, neurofibrillary tangles, synaptic disruption, and progressive neuronal deficits. The senile plaques contain amyloid-beta (1-42) and amyloid-beta (1-40), that has been shown by a number of laboratories to induce oxidative stress and as well as neurodegeneration, although the exact mechanisms remained to be defined. Our laboratory showed an increased oxidative stress in AD and MCI brain as indexed by protein oxidation and lipid peroxidation. In the present review, we summarize our finding of oxidatively modified proteins using a redox proteomics approach in AD and MCI brain to investigate the mechanism that may be involved in MCI and AD pathogenesis and discuss our findings in terms of AD progression and pathogenesis.     

A new depsidone and antibacterial activities of compounds from Usnea undulata Stirton

Usnea undulata Stirton (Usneaaceae) is a fruticose lichen used locally in ethnoveterinary medicine to treat mammary infections in cattle while human beings use it for the treatment of wounds in Eastern Cape, South Africa. Bioactivity-guided fractionation of its extracts led to the isolation and characterization of a new depsidone, 2'-O-methylhypostictic acid (8), together with seven known compounds, i.e. methyl β-orsellinate, norstictic acid, menegazziaic acid, (+) usnic acid, hypoconstictic acid, salazinic acid, and galbinic acid. The structures of the compounds were elucidated on the basis of their spectral analysis including homo- and hetero-nuclear correlation NMR experiments (COSY, NOESY, HMQC, and HMBC) and mass spectra as well as by comparison with available data in the literature. The minimum inhibitory concentrations (MICs) values of the compounds against six bacteria were determined. Compound 8 showed inhibitory activity against Bacillus cereus, Bacillus subtilis, and Staphylococcus epidermidis with MICs of 31, 62.5, 62.5 μg/ml, respectively. (+) Usnic acid was most active against B. subtilis, B. cereus, Staphylococcus aureus, and Escherichia coli with MICs of 8, 8, 31, and 31 μg/ml, respectively, while other compounds exhibited moderate activity.