Radiotherapy is safe in patients with implantable cardiac devices. Analysis of a systematic interrogation follow-up.

INTRODUCTION: The number of patients who have a cardiac implantable electronic device (CIEDs) that undergo a course of radiotherapy is increasing due to the ageing population. The majority of clinical studies only evaluate any CIED malfunction at the end of a course of irradiation or in a case of there being symptoms of possible malfunction. As a result, little data has been collected on CIED status acquired during an active course of irradiation. MATERIAL AND METHODS: We aimed to evaluate the correct functioning of a CIED during a course of radiotherapy. So, a retrospective analysis was made of all patients having CIEDS in a single institution during their course of radiotherapy. All CIEDs were systematically checked before and during the course of radiotherapy according to the risk of device failure and patient dependence. RESULTS: Data was analysed from 56 patients (43 men, 13 women) with a mean age of 78.2 years, of whom 87.5% of the patients carried a pacemaker (PM), the 39% of the patients were PM dependent, and the remaining patients carried an implantable cardioverter-defibrillator (ICD). An observable dose of irradiation was evident in only 10 cases. 69.1% of the CIEDs were checked daily and the remainder were checked weekly. During the radiotherapy course, 82% of the patients did not complain of any cardiological event. The CIED of five patients experienced an increase in the threshold and, in another case, a sudden reduction in the duration of the battery was reported. Another patient with a CIED experienced a cardiac insufficiency episode triggered by a ventricular tachycardia. CONCLUSION: In conclusions, although adverse clinical events from exposure of a CIED to irradiation are rare, they can appear in any group of risk. No dose-dependency was observed on the malfunction of the CIED.

Simultaneous Biofortification of Wheat with Zinc, Iodine, Selenium, and Iron through Foliar Treatment of a Micronutrient Cocktail in Six Countries.

Field experiments were conducted on wheat to study the effects of foliar-applied iodine(I) alone, Zn (zinc) alone, and a micronutrient cocktail solution containing I, Zn, Se (selenium), and Fe (iron) on grain yield and grain concentrations of micronutrients. Plants were grown over 2 years in China, India, Mexico, Pakistan, South Africa, and Turkey. Grain-Zn was increased from 28.6 mg kg-1 to 46.0 mg-1 kg with Zn-spray and 47.1 mg-1 kg with micronutrient cocktail spray. Foliar-applied I and micronutrient cocktail increased grain I from 24 µg kg-1 to 361 µg kg-1 and 249 µg kg-1, respectively. Micronutrient cocktail also increased grain-Se from 90 µg kg-1 to 338 µg kg-1 in all countries. Average increase in grain-Fe by micronutrient cocktail solution was about 12%. The results obtained demonstrated that foliar application of a cocktail micronutrient solution represents an effective strategy to biofortify wheat simultaneously with Zn, I, Se and partly with Fe without yield trade-off in wheat.

Importance of CCL25 in the attraction of T cells and the role of IL-7 on the signaling pathways in intestinal epithelial cells.

We have demonstrated an inflammatory process triggered by a dietary antigen accompanied with an increase of TNF-α in an experimental model of secondary immunodeficiency. TNF-α regulates the increase of γδ T subpopulation both in lamina propria and in the intestinal intraepithelium, where IL-7 influences γδ T cells development. TECK (CCL25)is important in the attraction and generation of T and B lymphocytes to the small intestine, lamina propria and intraepithelium. In the present study we evaluate CCL25 and IL-7 mRNA levels, by semiquantitative RT-PCR in intestinal epithelial cells. Lower levels of CCL25 mRNA were detected in animals after re-feeding compared to the well-nourished ones (P< 0.05), whereas an increase of 1.5 fold of IL-7 mRNA was registered in the experimental group (P < 0.05).When studying the intestinal epithelial cell distribution of the transcriptional factors NF-kB and Stat3,they were predominantly accumulated in the nucleus of cells isolated from the malnourished group, whereas they remain in the cytosol of the control one. The finding of an apoptosis decrease in intestinal epithelial cells isolated from malnourished animals was in agreement with the increased amount of Bcl-2 found in the mitochondrial fraction of this experimental group. All the above findings may lead us to conclude that we are in the presence of a mechanism by which γδ + T cells are increased in the intestinal villi, through different signaling path ways mediated by CCl25 and IL-7.

Early pulmonary response in rats infected with Trichinella spiralis.

The migratory stage of Trichinella spiralis, the newborn larva, travels along the pulmonary microvascular system on its way to the striated muscle cells. In the present study, an important inflammatory reaction was observed on days 5 and 14 post-infection (p.i.) in the lungs of infected rats. This inflammation was characterized by a Th2 cell phenotype of hyperplastic bronchus-associated lymphoid tissue and by goblet cell hyperplasia. Among the inflammatory cells were eosinophils and mast cells scattered over the pulmonary parenchyma. On day 5 p.i. the number of IgE(+), CD4(+) and CD5(+) cells in the bronchus-associated lymphoid tissue were increased and IgE-secreting lung cells were also detected. At the end of the migratory phase of the infection (day 14 p.i.), only IgE(+) cells were detected in high numbers and in the bronchoalveolar lavage fluid, an increment in the total IgE levels as well as the presence of IgE and IgA anti-larvae surface were also detected. In cytotoxicity assays, cells from the bronchoalveolar lavage had considerable biological activity since they were able to kill the larvae even in the absence of specific antibodies. These results show that the lung is an organ involved in the immune response developed early during a T. spiralis infection and suggest its importance in the protection of the host.

Compartmentalisation between gut and lung mucosae in a model of secondary immunodeficiency: effect of thymomodulin.

UNLABELLED: Compartmentalisation of mucosal immune response seems to be the result mainly of the preferential migration of activated cells back to their inductive sites. The aim of this report was to demonstrate, in a model of secondary immunodeficiency in Wistar rats (severely protein deprived at weaning and refed with casein 20%; group R21), that the oral administration of Thymomodulin (group:R21TmB) has different effects on gut and BALT (Bronchus-associated lymphoid tissue). Tissue sections (5 mu) were studied by immunohistochemistry 1). The oral administration of Thymomodulin restores only in gut Lamina propria (LP) the IgA B and CD4 T cell populations to control levels. The CD8a and CD25 subpopulations do not vary in gut as they return to control levels when refed with 20% casein diet. All the populations mentioned above remained decreased even after receiving Thymomodulin by the oral route. However, the same behaviour was observed for the TCR delta T cells that were decreased and return to normal levels in both mucosae by the effect of the immunomodulator; 2) when studying the iIEL (intestinal intraepithelial lymphocytes) CD8 alpha, CD25 and TCR gamma delta T cells, that were increased in R21, return to control levels in R21TmB. In BALT intraepithelium CD8 alpha and CD25 T cells remained decreased, while only TCR gamma delta T cells (increased in R21) return to control values. CONCLUSIONS: 1) there exists a compartmentalisation between both mucosae, as T CD4+ and IgA B+ cells are restored by TmB only in gut; 2) only those iIEL involved in inflammation (CD8 alpha+/CD25+ and TCR gamma delta+/CD25+) are normalised by means of the Thymomodulin 3) however, in BALT,only TCR gamma delta+ T cells are restored 4) the oral administration of the present immunomodulator may be useful as a therapeutic agent, although the preferential survival in the tissue of initial stimulation is the major factor in the preferential distribution of activated cells.

Oral tolerance to dextrin mediated by specific suppressor T-cells induced in the intestinal intraepithelium and their systemic migration.

Antigens presented to the immune system through the oral route induce antigen specific secretory IgA and systemic unresponsiveness, termed oral tolerance (OT). We studied the induction of OT towards a diet antigen: dextrin (DEX) in rats that underwent protein deprivation and were further re-fed. Peyer's patches (PP), mesenteric lymph nodes (MLN) and spleen (Sp) cells from protein re-fed (R) rats mediated hyporesponsiveness after transfer into naïve recipient rats. Low numbers of MLN T cells transferred hyporesponsiveness while higher numbers transferred an enhancement of the delayed type hypersensitivity (DTH) reaction. MLN T cells were further separated based on their ability to bind Vicia villosa (VV). MLN VV- T cells, mainly CD8+, mediated hyporesponsiveness and MLN VV+ T cells (CD45RC+ CD4- CD8- cells) abrogated the hyporesponsiveness. Moreover, Sp DEX adherent T cells were mainly CD8+. Intestinal intraepithelial lymphocytes (iIELs) mainly CD8alpha+ gamma(delta)-TCR+ cells also inhibited the DTH response to DEX after transfer. The positive DTH response to another carbohydrate (levan) indicates the specificity of the suppression to dextrin. Therefore, our data indicate that after oral administration of DEX, two different populations of T cells were generated: one found only in the MLN that mediated DTH responses and the other one capable of migrating from the intestinal intraepithelium through PP and MLN to the Sp, mediating systemic tolerance.

Cytogenetic studies in bone marrow cells from Wistar rats in protein malnutrition.

The effect of severe protein deficiency at weaning has been studied in bone marrow, which is a primary lymphoid organ. Our experimental model of secondary immunodeficiency in Wistar rats has shown: (1) a decreased number of viable bone marrow cells (P <.0001); (2) diminished percentage of mitosis (P <.01); and (3) severe alteration in the percentage of chromosome pairs 3, 11, and 12 bearing nucleolar organizer regions (NORs) (P <.05). This last finding indicates a poor ribosomal gene activity. These alterations were reverted after the oral administration of a 20% casein diet during 5 to 9 days. However, there were no karyotype variations between the experimental groups. We conclude from these results that severe protein deficiency at weaning alters several aspects of bone marrow cell proliferation and ribosomal gene activity as determined by the number of silver stained nucleolus organizer regions.

Nutrition disorders and immunologic parameters: study of the thymus in growing rats.

OBJECTIVES: We studied the effect of a low-quality dietary protein on cellular proliferation and maturation in the thymus of growing rats over time. METHODS: After weaning Wistar rats were fed a diet containing 6.5 g/100 g of corn flour for 6, 10, 18, and 45 d (M groups). For comparison, other rats were fed a diet containing 6.5 g/100 g of casein (Cas groups), and well-nourished age-matched control rats were fed a commercial laboratory diet (C groups). Food intake, body weight, thymus weight, total number of thymocytes, and the percentages of CD43(+) and Thy1(+) thymocyte phenotypic antigen determinants were measured. RESULTS: M versus Cas and C groups showed significant differences (P < 0.01) in body and thymus weights after 6 d of feeding, and the total number of thymocytes and the percentages of CD43(+) and Thy1(+) were significantly lower after 10 d of feeding. The results indicated that consuming a cereal diet for short or long periods causes thymus atrophy in growing rats, with significant reductions in the total number of T-cells concomitant with increases in the number of immature thymocytes. CONCLUSIONS: The data showed that, in addition to low-protein concentration, low-quality dietary protein is a limiting factor in certain steps of cellular intrathymic pathways, probably related to the requirement of specific amino acids for optimal immune response.

Hallazgos inmunohistoquímicos en material histopatológico de abortos recurrentes espontáneos / Immunohistochemical findings in histopathological material of spontaneous recurrent abortions

En 1994 en un estudio realizado por nuestro grupo en colabaración con la Dra. Fuksman sobre 1.200 placentas correspondientes a embarazos de alto riesgo, se halló la presencia de villitis en el 5.6 por ciento de las mismas. La histopatología detectada en ese momento fue deciduitis linfocitaria y aumento de fibrina perirvellositaria asociada con hipoirrigación e infarto placentario. Hallamos que en el 55 por ciento de las placentas con villitis los recién nacidos presentaban RCIU con respecto al 10 por ciento de los controles, con un PA de 32 por ciento en las villitis y el 83 por ciento en los controles (3). En ese material se estudiaron 68 placentas con villitis y 68 placentas sin villitis como grupo control. En 1996 demostramos en ese mismo material mediante la técnica de anticuerpos monoclonales, sobre cortes de placenta estudiando las subpoblaciones linfocitarias de las villitis, que el 50 por ciento eran CD4 (linfocitos helper), 18 por ciento CD8 (linfocitos supresoreslcitotóxicos) y 10 por ciento Leu19 (Natural Killer) pero lo significativo y anormal es que hallamos que el 65 por ciento de los linfocitos expresaban antígenos de histocompatibilidad clase II DR (40). En 1998 Jacques y Col publicaron datos similares. En 1999 comunicamos que en el informe histopatológico de material de legrado de pacientes abortadoras de causa inmunológica la descripción de villitis en un 20 por ciento de los casos. Estudios realizados en colabaración con la Dra. Zenclussen con ese material nos permitió publicar recientemente la presencia de altos niveles de Interleuquina 6(IL-6) y receptor de IL-6 en suero. El objetivo de este estudio es investigar en placentas de pacientes abortadoras recurrentes la expresión de IL-6 y sus receptores gp80 y gp130 en trece muestras de material de raspado de abortos del primer trimestre mediante la técnica de inmunofluorescencia. Como control se utilizaron cortes de placentas de embarazos normales a término. Nuestros hallazgos muestran la presencia de depósitos de IL-6 y de receptores de IL-6 con un patrón granular para las tres moléculas especificamente en el sinciciotrofoblasto mientras que fue negativo para tres en el citotrofoblasto. En los cortes de placentas normales no se hallaron en ningún caso dichos depósitos. Concluímos de todos los hallazgos antes sintetizados...(AU)

Hallazgos inmunohistoquímicos en material histopatológico de abortos recurrentes espontáneos / Immunohistochemical findings in histopathological material of spontaneous recurrent abortions

En 1994 en un estudio realizado por nuestro grupo en colabaración con la Dra. Fuksman sobre 1.200 placentas correspondientes a embarazos de alto riesgo, se halló la presencia de villitis en el 5.6 por ciento de las mismas. La histopatología detectada en ese momento fue deciduitis linfocitaria y aumento de fibrina perirvellositaria asociada con hipoirrigación e infarto placentario. Hallamos que en el 55 por ciento de las placentas con villitis los recién nacidos presentaban RCIU con respecto al 10 por ciento de los controles, con un PA de 32 por ciento en las villitis y el 83 por ciento en los controles (3). En ese material se estudiaron 68 placentas con villitis y 68 placentas sin villitis como grupo control. En 1996 demostramos en ese mismo material mediante la técnica de anticuerpos monoclonales, sobre cortes de placenta estudiando las subpoblaciones linfocitarias de las villitis, que el 50 por ciento eran CD4 (linfocitos helper), 18 por ciento CD8 (linfocitos supresoreslcitotóxicos) y 10 por ciento Leu19 (Natural Killer) pero lo significativo y anormal es que hallamos que el 65 por ciento de los linfocitos expresaban antígenos de histocompatibilidad clase II DR (40). En 1998 Jacques y Col publicaron datos similares. En 1999 comunicamos que en el informe histopatológico de material de legrado de pacientes abortadoras de causa inmunológica la descripción de villitis en un 20 por ciento de los casos. Estudios realizados en colabaración con la Dra. Zenclussen con ese material nos permitió publicar recientemente la presencia de altos niveles de Interleuquina 6(IL-6) y receptor de IL-6 en suero. El objetivo de este estudio es investigar en placentas de pacientes abortadoras recurrentes la expresión de IL-6 y sus receptores gp80 y gp130 en trece muestras de material de raspado de abortos del primer trimestre mediante la técnica de inmunofluorescencia. Como control se utilizaron cortes de placentas de embarazos normales a término. Nuestros hallazgos muestran la presencia de depósitos de IL-6 y de receptores de IL-6 con un patrón granular para las tres moléculas especificamente en el sinciciotrofoblasto mientras que fue negativo para tres en el citotrofoblasto. En los cortes de placentas normales no se hallaron en ningún caso dichos depósitos. Concluímos de todos los hallazgos antes sintetizados...

Flow cytometric analysis of intestinal intraepithelial lymphocytes in a model of immunodeficiency in Wistar rats.

BACKGROUND: We have shown, in a rat model of immunodeficiency, permanent alterations in the thymus and in the gut-associated lymphoid tissues. We observed by immunohistochemistry an increase in the number of gamma/delta+ T cells in the gut lamina propria and in the number of CD8alpha/alpha+, CD25+, gamma/delta+ subpopulations of intestinal intraepithelial lymphocytes (iIEL). The aim of the present study was to analyze the isolated rat iIEL by flow cytometry. Materials and Methods Cells from mesenteric lymph nodes were examined in parallel with isolated iIEL. After staining with different antibodies, samples were run on a FACScan flow cytometer. Background staining was evaluated using isotype controls. Data analysis was performed using Lysys II software (Becton Dickinson) and WinMDI 2.3 software. RESULTS: 1) CD8alpha/beta populations do not express TCRgamma/delta, 2) CD8alpha/alpha+ populations express TCRgamma/delta, and its percentage is significantly increased in R21, 3) CD8alpha/beta and CD8alpha/alpha iIEL express TCRalpha/beta, being the percentage of CD8alpha/alpha+ TCRalpha/beta+ iIEL increased and the percentage of CD8alpha/beta+ TCRalpha/beta+ iIEL decreased in R21, and 4) CD8alpha/alpha as well as CD8alpha/beta iIEL do express CD25 only in R21. CONCLUSIONS: Considering the above results, we conclude that there exists an "in situ" origin and extrathymic maturation of the CD8alpha/alpha+ iIEL in the intestinal epithelium. The increase of TCRgamma/delta+ T cells may be triggered by the carbohydrate dextrin, to provide immune protection and control of inflammation at the intestinal level.

Developmental study of immunocompetent cells in the bronchus-associated lymphoid tissue (BALT) from Wistar rats.

The aim of the present report was to study in growing Wistar rats the development of immunocompetent cells in the bronchus-associated lymphoid tissue (BALT). We found at day 4 postpartum, a high number of TCRgamma/delta+ T cells and very few CD8alpha+, CD8beta+, CD5+, TCRalpha/beta+ T cells in BALT. The latter cells and CD4+ T cells increase with age. Even though T cells expressing TCRgamma/delta outnumber those expressing TCRalpha/beta early in development, until 45 days of age, alpha/beta+ predominate over gamma/delta+ T cells only in adult rats (60 days of age). Moreover, a predominance of suppressor/cytotoxic T cells over T-helper cells was found in 60 days old rats. Surprisingly, more CD8alpha+ than CD8beta+ T cells in BALT are observed. The number of IgA+ B and CD4+ T cells found in the BALT increases with age. The early appearance - 4 days of age - of all T-cell phenotypes in BALT especially of gamma/delta+ T cells may imply a benefit to respond to inhaled antigen soon after birth.

IgA B and T cells in the intestinal Villi of immunodeficient rats orally treated with thymomodulin.

Previous studies on the effect of the oral administration of bacterial immunomodulators (1M-104 and RN-301) during the protein free diet period, have shown an increase on B and T cell gut repopulation, accompanied by IgA antibody production. The usefulness of oral administration of the immunomodulator thymomodulin (TmB) during the protein refeeding period was investigated. TmB allowed the recovery of a normal repopulation of gut lamina propria with IgA B and CD5 T cells and decreases to control values the number of activated intraepithelial lymphocytes (CD25+ T cell subset). Therefore, the oral administration of TmB may be useful as a therapeutic agent as it seems to improve the repopulation of intestinal villi with immunocompetent cells. Also, it seems to regulate the immunosurveillance at the epithelium level as it increases the CD5+ T cells but decreases the activated ones.

Recombinant tissue-type plasminogen activator therapy of thrombosis in 16 neonates.

We report 16 cases of neonatal vascular thrombosis treated with the same protocol for recombinant tissue-type plasminogen activator infusion. Flow restoration was complete in seven patients, partial in seven, and absent in two. Safety was satisfactory provided contraindications were respected.

Effect of RN-301 immunomodulator on bronchus-associated lymphoid tissue (BALT) in protein depleted rats at weaning.

It has been previously demonstrated in Wistar rats that severe protein deprivation at weaning, even after refeeding with a 20% casein diet for 21 days, provokes alterations in IgA+ B cell and T cell populations from gut and GALT (gut associated lymphoid tissue) that are reverted by immunomodulator IM-104. In the present report, we investigate the influence of RN-301 (quite similar to IM-104) given by the oral or subcutaneous route during the protein deprivation period, in the seeding of BALT with IgA+ B and CD5+ T cells. The immunomodulator RN-301 contains LPS from E. coli and membrane and ribosomal fractions of P. acne. Tissue sections of the lower respiratory tract were studied by immunohistochemistry. The immunomodulator RN-301 administered by the oral route favours the significant increase in the seeding of the BALT lamina propria with IgA+ B and CD5+ T cells (p < 0.001). However, the RN-301 given by the subcutaneous route does not favour the repopulation of the BALT lamina propria. The ribosomal fractions from P. acne associated with LPS from E. coli contained in the immunomodulator RN-301 administered by the oral route may rescue the small resting lymphocytes in the gut-associated lymphoid tissue (GALT). This event favours their proliferation and migration to the BALT.

Oral administration of a bacterial immunomodulator enhances the immune response to cholera toxin.

Attempts to achieve IgA responses in the intestine by oral immunization with non replicating antigens have been characterized by ineffective responses of short duration unless long term dosages are administered. Cholera toxin (CT) is an exception in that it is able to produce a high secretory and systemic immune response. We study the effects of a bacterial immunomodulator [3 x 10(10) Propionibacterium granulosum ml-1 and lipopolysaccharide (LPS) 5 mg ml-1] on the immune response to CT orally administered to Wistar rats. The immunomodulator was orally administered as follows: in schedule 1 during 7 days prior to the first dose of CT; and in schedule 2, 2 days before, together, and 3 days after the first dose of CT. Schedules 1 and 2 were effective in increasing the specific IgA in the intestinal fluid and specific IgG in serum (P < 0.001) when compared to controls. Besides, schedule 2 was more effective than schedule 1 when the levels of specific IgG in serum or specific IgA in intestinal fluid was measured (P < 0.05). Total IgA in the intestinal fluid was increased in rats receiving the immunomodulator (P < 0.01). However, the ratio of specific IgA per total IgA was higher in rats receiving treatment 1 or 2 when compared to controls (P < 0.01). The number of antitoxin antibody producing cells was not increased in the Peyer patches, but a significant increase was observed in the mesenteric lymph nodes and spleen when compared to controls (P < 0.05). The administration of LPS alone produced an increase in the antitoxin immune response when compared to controls, but it was lower than those produced by the administration of the immunomodulator. These results indicate that this immunomodulator is an effective adjuvant of the mucosal and systemic immune response to CT. The mechanisms of action possibly involve nonespecific and specific modulations of the immune response.

Study on possible increase in twinning rate at a small village in south Brazil.

A high frequency of twin births has been observed in Linha São Pedro, a small settlement which belongs to the city of Cãndido Godói, located 524 km Northwest from Porto Alegre, Rio Grande do Sul, Brazil, in an ethnically homogeneous population of German descent restricted to a small geographic region. From 1990 to 1994, the proportion of twin births in Linha São Pedro was 10%, significantly higher than the 1.8% rate for the state of Rio Grande do Sul as a whole. Genealogical analysis showed a high recurrence of multiple births within families, as well as a high level of inbreeding in the community. Zygosity data indicated that 9 of the 17 pairs of twins studied (53%) were dizygotic. No external environmental factors were detected that could be influencing the appearance of this characteristic. This preliminary investigation confirmed the presumed existence of a high twinning rate in the community. The high familial recurrence and the high inbreeding rate suggests the presence of genetic twinning factors. Complementary studies of twins that have yet to be evaluated and the search for additional risk factors, as well as linkage studies, should contribute to a further understanding of the biological factors related to twin births in the human species.