A Rat Treated with Mesenchymal Stem Cells Lives to 44 Months of Age.

There is a growing interest in the potential of mesenchymal stem cells (MSCs) for implementing regenerative medicine. We assessed the effect of intravenous administration of human bone marrow-derived MSC on the life span of a single Sprague-Dawley female rat. The treatment was started when the rat was 6 months old and the cells were administered every 2 weeks afterward. The treatment did not induce any obvious changes in body growth or behavior and the rat showed the typical age changes for this strain, except that, unlike intact counterparts, the animal did not develop mammary tumors or pituitary gland hyperplasia. The more remarkable effect of the treatment was on life span, which was 44 months compared with an average of 36 months for intact laboratory rats. We conclude that despite the low N value, it is likely that the MSC treatment was responsible for the exceptionally long survival of the rat. The potential rewards of confirming the present findings warrant further studies involving higher N values.

Racemized and Isomerized Proteins in Aging Rat Teeth and Eye Lens.

The quantification of aspartic acid racemization in the proteins of nonmetabolically active tissues can be used as a measure of chronological aging in humans and other long-lived organisms. However, very few studies have been conducted in shorter-lived animals such as rodents, which are increasingly used as genetic and metabolic models of aging. An initial study had reported significant changes in the ratio of d- to l-aspartate in rat molars with age. Using a sensitive HPLC method for the determination of d- and l-aspartate from protein hydrolysates, we found no accumulation of d-aspartate in the molars of 17 rats that ranged in age from 2 to 44 months, and the amount of d-aspartate per molar did not correspond with molar eruption date as had been previously reported. However, developing an alternate approach, we found significant accumulation of isomerized aspartyl residues in eye lens proteins that are also formed by spontaneous degradation processes. In this study, we used the human protein l-isoaspartate/d-aspartate O-methyltransferase (PCMT1) as an analytical reagent in a sensitive and convenient procedure that could be used to rapidly examine multiple samples simultaneously. We found levels of isomerized aspartyl residues to be about 35 times higher in the lens extracts of 18-month-old rats versus 2-month-old rats, suggesting that isomerization may be an effective marker for biological aging in this range of ages. Importantly, we found that the accumulation appeared to plateau in rats of 18 months and older, indicating that potentially novel mechanisms for removing altered proteins may develop with age.

Cadaveric bone marrow mesenchymal stem cells: first experience treating a patient with large severe burns.

BACKGROUND: In January 2005, Rasulov et al. originally published "First experience in the use of bone marrow mesenchymal stem cells (MSCs) for the treatment of a patient with deep skin burns". Here, we present the first ever treated patient with cadaveric bone marrow mesenchymal stem cells (CMSCs) in the history of Medicine. METHODS: A young man, who severely burned 60 % of his total body surface with 30 % of full-thickness burns while working with a grass trimmer that exploded, was involved in the study. MSCs were obtained from the bone marrow of a cadaver donor in a routine procurement procedure of CUCAIBA, the Province of Buenos Aires, Argentina, Ministry of Health, Transplantation Agency, cultured, expanded, and applied on the burned surfaces using a fibrin spray after early escharotomy. RESULTS: So far, our preliminary experience and our early results have been very impressive showing an outstanding safety data as well as some impressive good results in the use of CMSCs. CONCLUSIONS: Based on all this, we think that improvements in the use of stem cells for burns might be possible in the near future and a lot of time as well as many lives could be saved by many other research teams all over the world. CMSCs will probably be a real scientific opportunity in Regenerative Medicine as well as in Transplantation.

Enhanced singlet oxygen production by photodynamic therapy and a novel method for its intracellular measurement.

The generation of singlet oxygen (SO) in the presence of specific photosensitizers (PSs) or semiconductor quantum dots (QDs) and its application in photodynamic therapy (PDT) is of great interest to develop cancer therapies with no need of surgery, chemotherapy, and/or radiotherapy. This work was focused on the identification of the main factors leading to the enhancement of SO production using Rose Bengal (RB), and Methylene Blue (MB) as PS species in organic and aqueous mediums. Subsequently, the capacity of zinc oxide (ZnO), zinc sulfide (ZnS), and ZnO/ZnS core-shell QDs as well as manganese (Mn(+2)) doped ZnO and ZnS nanoparticles (NPs) as potential PS was also investigated. Many variable parameters such as type of quencher, PSs, NPs, as well as its different concentrations, light source, excitation wavelength, reaction time, distance from light source, and nature of solvent were used. The degradation kinetics of the quenchers generated by SO species and the corresponding quantum yields were determined by monitoring the photo-oxidation of the chemical quencher and measuring its disappearance by fluorometry and spectrophotometry in the presence of NPs. Small intracellular changes of SO induced by these metal Zn (zinc) NPs and PDT could execute and accelerate deadly programs in these leukemic cells, providing in this way an innovative modality of treatment. In order to perform further more specific in vitro cytotoxic studies on B-chronic lymphocytic leukemia cells exposed to Zn NPs and PDT, we needed first to measure and ascertain those possible intracellular SO variations generated by this type of treatment; for this purpose, we have also developed and tested a novel method first described by us.

New potential therapeutic approach for the treatment of B-Cell malignancies using chlorambucil/hydroxychloroquine-loaded anti-CD20 nanoparticles.

Current B-cell disorder treatments take advantage of dose-intensive chemotherapy regimens and immunotherapy via use of monoclonal antibodies. Unfortunately, they may lead to insufficient tumor distribution of therapeutic agents, and often cause adverse effects on patients. In this contribution, we propose a novel therapeutic approach in which relatively high doses of Hydroxychloroquine and Chlorambucil were loaded into biodegradable nanoparticles coated with an anti-CD20 antibody. We demonstrate their ability to effectively target and internalize in tumor B-cells. Moreover, these nanoparticles were able to kill not only p53 mutated/deleted lymphoma cell lines expressing a low amount of CD20, but also circulating primary cells purified from chronic lymphocitic leukemia patients. Their safety was demonstrated in healthy mice, and their therapeutic effects in a new model of Burkitt's lymphoma. The latter serves as a prototype of an aggressive lympho-proliferative disease. In vitro and in vivo data showed the ability of anti-CD20 nanoparticles loaded with Hydroxychloroquine and Chlorambucil to increase tumor cell killing in comparison to free cytotoxic agents or Rituximab. These results shed light on the potential of anti-CD20 nanoparticles carrying Hydroxychloroquine and Chlorambucil for controlling a disseminated model of aggressive lymphoma, and lend credence to the idea of adopting this therapeutic approach for the treatment of B-cell disorders.

Could metabolic syndrome, lipodystrophy, and aging be mesenchymal stem cell exhaustion syndromes?

One of the most important and complex diseases of modern society is metabolic syndrome. This syndrome has not been completely understood, and therefore an effective treatment is not available yet. We propose a possible stem cell mechanism involved in the development of metabolic syndrome. This way of thinking lets us consider also other significant pathologies that could have similar etiopathogenic pathways, like lipodystrophic syndromes, progeria, and aging. All these clinical situations could be the consequence of a progressive and persistent stem cell exhaustion syndrome (SCES). The main outcome of this SCES would be an irreversible loss of the effective regenerative mesenchymal stem cells (MSCs) pools. In this way, the normal repairing capacities of the organism could become inefficient. Our point of view could open the possibility for a new strategy of treatment in metabolic syndrome, lipodystrophic syndromes, progeria, and even aging: stem cell therapies.

Exploratory study on the effects of biodegradable nanoparticles with drugs on malignant B cells and on a human/mouse model of Burkitt lymphoma.

The aim of this study was to determine if Rituximab coated Biodegradable Nanoparticles (BNPs) loaded with Chlorambucil and Hydroxychloroquine could induce apoptosis of B-Chronic Lymphocytic Leukemia (B-CLL), MEC-1 and BJAB cells in vitro and evaluate their toxic and therapeutic effects on a Human/Mouse Model of Burkitt Lymphoma at an exploratory, proof of concept scale. We found that Rituximab-Chlorambucil-Hydroxychloroquine BNPs induce a decrease in cell viability of malignant B cells in a dose-dependent manner. The mediated cytotoxicity resulted from apoptosis, and was confirmed by monitoring the B-CLL cells after Annexin V/propidium iodide staining. Additional data revealed that these BNPs were non toxic for healthy animals, and had prolonged survival in this mice model of human lymphoma.

The lysosomotropic agent, hydroxychloroquine, delivered in a biodegradable nanoparticle system, overcomes drug resistance of B-chronic lymphocytic leukemia cells in vitro.

Nonviral delivery systems are relatively easy to produce in the large scale, are safe, and elicit a negligible immune response. Nanoparticles (NPs) offer promise as nonviral vectors as biocompatible and -degradable carriers of drugs with targeting to specific sites by surface receptors of monoclonal antibodies (mAbs). We investigated the effect of four PEG-PLGA (polyethylene glycol-polylactic-co-glycolic acid) NP systems on drug-resistant B-chronic lymphocytic leukemia (B-CLL) cells in vitro, three of them encapsulating the drug, hydroxylchloroquine (HDQ), two with NP surface coatings of mAbs (NP1) CD20, (NP2) CD19, and CD20, and one (NP3) with no mAb, but tagged with the fluorescent marker, fluorescein isothiocyanate. The fourth NP system (NP4) was coated with anti-CD19/FITC and anti-CD20/Alexa-Fluor((R)) antibodies, but did not contain the active drug, HCQ. Our data indicate that PEG-PLGA nanoparticles with surface mAbs are suitable for selective drug delivery to B-CLL cells and produce a strong apoptotic effect when loaded with the lysosomotropic agent, HDQ.

Apoptosis induced by Magnolia Grandiflora extract in chlorambucil-resistant B-chronic lymphocytic leukemia cells.

BACKGROUND: B-cell chronic lymphocytic leukemia (B-CLL) still remains as an uncurable disease. Even the newest antineoplastic agents have demonstrated limitations in their efficacy. For this reason, further research of new compounds must be done. New pharmacological properties can be obtained from a great diversity botanical species. Among these products, Magnolia Grandiflora receives our attention since it mainly contains Honokiol which had demonstrated effect against B-CLL cells activating different cell death pathways. AIM: To test the ability of Magnolia Grandiflora extracts to induce apoptosis of B-CLL cells in vitro. MATERIALS AND METHODS: Herb's extraction: Twenty grams of powdered material were submitted to three consecutives decoctions with 500 ml of distilled water (96 °C), filtered and followed by ultrafiltration with cellulose membrane, lyophilized and reconstituted in AIM-V medium at a final concentration of 10 mg/ml solution. B-CLL chlorambucil-resistant cells were separated and cultivated in the presence of Magnolia's extract. Samples of cells were taken from the cultures at 24, 48 and 72 h for apoptosis analysis by flow cytometry measuring positive annexin V (0.1 µg/ml) cells. STATISTICS: Apoptosis values were represented by the mean plus or minus SD (± SD) for five independent experiments. Statistical significance was determined by Student's t-test. A P value of 0.05 or less was considered as significant. RESULTS AND CONCLUSION: This article discusses the apoptosis properties of Magnolia on B-CLL cells. The evidence suggests a potentially effective repertoire for B-CLL treatment. This herb extract might have promising therapy strategies in treating B-CLL or other hematological disease resistant to alkylating agents in clinical practice.

Feasibility investigation of allogeneic endometrial regenerative cells.

Endometrial Regenerative Cells (ERC) are a population of mesenchymal-like stem cells having pluripotent differentiation activity and ability to induce neoangiogenesis. In vitro and animal studies suggest ERC are immune privileged and in certain situations actively suppress ongoing immune responses. In this paper we describe the production of clinical grade ERC and initial safety experiences in 4 patients with multiple sclerosis treated intravenously and intrathecally. The case with the longest follow up, of more than one year, revealed no immunological reactions or treatment associated adverse effects. These preliminary data suggest feasibility of clinical ERC administration and support further studies with this novel stem cell type.

Aspectos moleculares de los procesos autoinmunes en diabetes tipo 1 / Molecular aspects of the autoimmunes processes in diabetes type I

Evidences of the relationship between immunological disturbances and diseases are more conclusive every day. IDDM is a good example of an autoimmunne process associated with a severe clinical picture.

Aspectos moleculares de los procesos autoinmunes en diabetes tipo 1 / Molecular aspects of the autoimmunes processes in diabetes type I

Evidences of the relationship between immunological disturbances and diseases are more conclusive every day. IDDM is a good example of an autoimmunne process associated with a severe clinical picture. (AU)

Tesis universitarias sobre el niño: 20 años de trabajo académico en ciencias sociales / Academic dissertations about children: 20 years of academic work in social sciences

El tema "niño de la calle" es netamente urbano y tiene correspondencia con la problemática de la migración y el desarrollo de los pueblos jóvenes, así como el auge del sector informal de la economía urbana. Esta búsqueda bibliográfica abarca desde 1965 hasta 1985 de producción académica. En este documento se presenta la información recuperada, tematizadas en tres grandes categorías: Niño y adolescente; Familia; Comunidad, todas precedidas de un breve análisis y comentario