New dithiolopyrrolone antibiotics from Saccharothrix sp. SA 233. I. Taxonomy,fermentation, isolation and biological activities

Three new natural antibacterial and antifungal dithiolopyrrolone antibiotics were isolated along with the known iso-butyropyrrothine and thiolutine from the fermentation broth of an actinomycete strain which was isolated from a saharian palm grove soil collected at Adrar, south Algeria. The strain was identified as Saccharothrix sp. The three new antibiotics exhibited broad antimicrobial activity against gram-positive bacteria, yeasts and fungi in vitro.     

Monitoring of two intravenous immunoglobulin. Preparations for immunoglobulin G subclasses and specific antibodies to bacterial surface antigens and relation with their levels in treated immunodeficient patients

Patients with antibody deficiency disorders are highly susceptible to bacterial infections. Replacement therapy with intravenous immunoglobulin preparations (IVIG) has been established in such patients for two decades. The efficacy of IVIG treatment depends on the amount of functional pathogen-specific antibodies provided. The present study was undertaken to determine the levels of immunoglobulin classes, IgG subclasses, and specific antibodies to bacterial surface antigens in two different IVIG preparations (Sandoglobulin® and Gamimmune®) and blood sera of IVIG-treated immunodeficient patients. The levels of IgG, IgA, IgM and IgG subclasses were determined in both IVIG preparations and in patients’ sera and were compared with those of healthy individuals. Sandoglobulin® contained significantly higher concentrations of IgA, IgG₂ and IgG₄ than Gamimmune®. The latter contained higher concentrations of IgG₁. Patients treated with Gamimmune® had significantly lower concentration of IgG₄ as compared with healthy individuals and Sandoglobulin®-treated patients. This finding was related to the preparation’s composition. Screening of 20 lots from each preparation for antibodies to frequent clinically isolated strains of Escherichia coli, Staphylococcus aureus, S. epidermidis, Klebsiella pneumoniae and Enterococci spp. showed a high lot-to-lot variability. In order to overcome the lot-to-lot variability and correlate the observed effects with each IVIG preparation, the administered IVIG lots were selected so that their titers were in the interval of mean value±S.D. for each pathogen. The two tested preparations showed significant differences in their content of specific antibodies that ultimately affected the levels of these antibodies in treated patients. More specifically, Sandoglobulin® contained higher levels of antibodies to E. coli and S. epidermidis strains. Infusion of this preparation maintained the respective antibodies in the recipients significantly higher than those of healthy individuals. Gamimmune® infusion led to similar and comparable levels. Both IVIG preparations had comparable antibody titers towards K. pneumoniae, provided high amounts of antibodies, and kept recipients’ specific IgG at levels significantly higher than those of the healthy individuals. Enterococci spp. specific antibodies were significantly higher in Gamimmune®, whereas titers of antibodies towards S. aureus were comparable. Levels of antibodies against both Enterococci spp. and S. epidermidis after administration of both preparations were close to those in healthy individuals. None of the patients developed infection during the time of the study. In conclusion, most of the lots of the two IVIG preparations studied, despite some quantitative differences, provide patients with sufficient amounts of antibodies to bacterial surface antigens that protect them against infections.     

Involvement of the optic nerve in the course of Behcet's disease (presentation of 148 cases)

Beh?et's disease is a multisystemic vascularitis of still unknown etiopathogeny. Among 400 cases of Beh?et disease, 148 cases presented an optic nerve involvement during a period of eight years (1992-1999). The goal of this work is to contribute to the study of optic nerve involvement in Beh?et's disease. The involvement is higher in males (64%) with median age of 27 years. The involvement of the optic nerve is noticed in 37% of cases. It's isolated in 7% of cases and occurs on average after 5 years of evolution of the disease. The diagnosis is based on the clinical examination, visual field, visual evoked potentials, retinal angiography and neuro-imaging (TDM and/or MRI). It can be an acute anterior neuropathy, stasis papilledema complicating a benign intracranial hypertension, neuroretinitis or retrobulbar optic neuropathy. The extraocular systemic manifestations were dominated by oral aphthosis (94%), genital aphthosis (70%), joint manifestations (40%) and central nervous system involvement (32.4%). The prognosis is reserved, 44% of patients having vision lower than 1/10 in spite of treatment. The authors insist on the therapeutic emergency that this involvement represents and the interest to consider it in all patients having an unexplained visual loss.     

Large matrix proteoglycans,versican and perlecan,are expressed and secreted by human leukemic monocytes

THP-1 is a monocytic cell line originally derived from a patient with acute monocytic leukemia. Interactions of THP-1 cells with other cells and their microenvironment are largely determined by proteoglycans (PGs), the identity of which has not been determined. Previous studies on glycosaminoglycan expression by THP-1 cells and peripheral blood mononuclear cells from healthy individuals showed that both cell types secrete mainly chondroitin sulfate PGs to the culture medium, whereas heparan sulfate PGs are mainly retarded at the cell membrane. However, limited data on the type of PGs synthesized by THP-1 is available. In this study, the identification of PG types synthesised by THP-1 cells, which are not differentiated to macrophages, was examined. Analysis at the mRNA level by RT-PCR showed the expression of six cell membrane-associated PGs: syndecan-1, -2 and -4, glypican-1, thrombomodulin and CD44. Cell extraction, ion-exchange chromatography and dot blot analysis of the isolated PG populations with monoclonal antibodies showed the presence of syndecan-1 and thrombomodulin; the other two syndecans were not detected in any of the isolated populations. The synthesis of matrix PGs was also studied. THP-1 monocytes were positive for the mRNA encoding for versican and perlecan, but not for those encoding for decorin, biglycan, betaglycan and fibromodulin. The mRNA encoding for two versican splice variants V0 (351 bp) and V1 (386 bp), but not for V2, were identified. Biochemical analysis showed the presence of perlecan and of two populations of versican in culture medium with protein cores of average molecular sizes similar to those of V0 and V1. The production of these large matrix PGs by THP-1 monocytes is reported for the first time and may be of importance in monocyte malignant transformation and differentiation.     

An enzyme immunoassay to determine the levels of specific antibodies toward bacterial surface antigens in human immunoglobulin preparations and blood serum

Human polyvalent intravenous immunoglobulin (IVIG) preparations are used as a complementary aid to the proper antimicrobial treatment of severely septic patients in intensive care units (ICUs) and/or as a prophylactic agent to immunocompromized hosts, particularly prone to bacterial infections. There is skepticism about the usefulness of IVIGs since it is not known whether their administration ensures the enhancement of humoral immune responses by providing a sufficient amount of specific antibodies towards the specified bacterial pathogen to be treated. In this report, a simple and reproducible enzyme-linked immunosorbent assay for determining the content of specific antibodies against bacterial surface antigens in commercially available IVIG preparations is described. The method is also easily applied to determine the amount of bacterial antibodies in blood serum. The levels of specific antibodies toward Gram positive and negative pathogenic isolates often encountered in ICUs were estimated in two IVIG (Sandoglobulin® and Gamimmune®) preparations. Significant differences regarding the content of antibodies to certain clinically bacterial isolates were identified not only between the two IVIG preparations tested, but also among various lots from each IVIG preparation. No significant variation (P≤0.001) among the bottles derived from the same lot was determined in both preparations. The variation in the levels of specific antibodies in IVIG preparations may be attributed to differences between the donor pools as well as the manufacturing procedure. Application of the method to patients with primary immune deficiencies showed that infusion of highly reactive IVIG preparations enhanced significantly their humoral response toward various pathogens. The results of this study suggest that the content determination of pathogen-specific antibodies in IVIG preparations before administration may be of great importance for treating bacterial infections.     

The potential of chondroitin sulfate as a therapeutic agent

Chondroitin sulfate (CS) is an omnipresent glycosaminoglycan with significant biologic roles. Chondroitin sulfate has not one structure but its polysaccharide backbone is modified to a smaller or higher degree according to the cell, tissue, species localization, and/or physiopathological stimuli. The potential of chondroitin sulfate for the therapy of osteoarthritis has been under investigation in several clinical trials, which have shown that it is safe and well tolerated. However, there are many issues still unresolved, such as the structure-modifying effects of CS in osteoarthritis, symptom-modifying efficacy in certain groups of patients, structure-activity-pharmacokinetic relationships, knowledge of mechanism of action, and better quality control of the preparations. Furthermore, ongoing basic research on its biologic role will probably show other therapeutic applications.     

Distinct Patterns of Antiamyloid-β Antibodies in Typical and Atypical Alzheimer Disease

OBJECTIVE To compare serum antiamyloid-β (Aβ) antibodies in typical and atypical Alzheimer disease (AD). DESIGN Preliminary observations. SUBJECTS Thirteen patients with AD, 8 patients with posterior cortical atrophy with evidence of AD (PCA-AD) pathophysiological process by both cerebrospinal fluid (CSF) biomarkers and amyloid imaging, and 12 age-matched control individuals. INTERVENTIONS The class and subclass levels of serum anti-Aβ antibodies were measured using an oligomer-based enzyme-linked immunosorbent assay. This method allowed measuring both free antibodies and, after acidic treatment, the total fraction that includes all antibodies complexed with circulating Aβ40/42 and any cross-reacting antigen. RESULTS Anti-Aβ IgG were restricted to the IgG1 and IgG3 subclasses. Their total levels were strikingly lower and more homogeneous in patients with PCA compared with both typical AD and controls, while biomarkers of amyloid deposition (CSF Aβ42 and positron emission tomography amyloid imaging) were similar in patients with AD and patients with PCA. CONCLUSIONS Serum anti-Aβ IgG1 and IgG3 antibodies differ between distinct forms of AD. Its significance is discussed for possible implications as immune effectors in the specific pathophysiology of AD variants.     

Association of cerebrospinal fluid α-synuclein with total and phospho-tau181 protein concentrations and brain amyloid load in cognitively normal subjective memory complainers stratified by Alzheimer's disease biomarkers

Introduction

Several neurodegenerative brain proteinopathies, including Alzheimer's disease (AD), are associated with cerebral deposition of insoluble aggregates of α-synuclein. Previous studies reported a trend toward increased cerebrospinal fluid (CSF) α-synuclein (α-syn) concentrations in AD compared with other neurodegenerative diseases and healthy controls.

Cell-line specific protection by berry polyphenols against hydrogen peroxide challenge and lack of effect on metabolism of amyloid precursor protein

Amyloid precursor protein (APP) altered metabolism, Aβ‐overproduction/aggregation and oxidative stress are implicated in the development of Alzheimer's disease pathology. Based on our previous data indicating that administration of a polyphenol‐rich (PrB) blueberry extract (from wild Vaccinium angustifolium) is memory enhancing in healthy mice and in order to delineate the neuroprotective mechanisms, this study investigated the antioxidant effects of PrB in H₂O₂‐induced oxidative damage, Aβ peptide fibrillogenesis and APP metabolism. PrB suppressed H₂O₂‐initiated oxidation (DCF assay) and cell death (MTT assay) in SH‐SY5Y cells. Protective effects were observed on Chinese hamster ovary (CHO) cells overexpressing APP770 carrying the mutation Val717Phe only at high concentrations, while further damage on HEK293 cells was induced after co‐treatment with 250 µ m H₂O₂ and PrB in comparison with H₂O₂ alone. Using the thioflavine T assay, blueberry polyphenols inhibited Aβ‐aggregation (~70%, 15 µg/mL) in a time‐dependent manner, while in the CHO^APP770 cells it had no effect on APP metabolism as assessed by western blot. The results suggest that blueberry polyphenols exhibit antioxidant and/or pro‐oxidant properties according to the cellular environment and have no effect on APP metabolism. Copyright © 2011 John Wiley & Sons, Ltd.