Continuous intestinal infusion of levodopa-carbidopa in patients with advanced Parkinson's disease in Spain: Subanalysis by autonomous community. / Uso de la infusión intestinal continua de levodopa-carbidopa en pacientes con enfermedad de Parkinson avanzada en España. Subanálisis por comunidades autónomas.

OBJECTIVES: To compare the characteristics of patients undergoing treatment with continuous intestinal infusion of levodopa-carbidopa (CIILC) for advanced Parkinson's disease and the data on the effectiveness and safety of CIILC in the different autonomous communities (AC) of Spain. METHODS: A retrospective, longitudinal, observational study was carried out into 177 patients from 11 CAs who underwent CIILC between January 2006 and December 2011. We analysed data on patients' clinical and demographic characteristics, variables related to effectiveness (changes in off time/on time with or without disabling dyskinesia; changes in Hoehn and Yahr scale and Unified Parkinson's Disease Rating Scale scores; non-motor symptoms; and Clinical Global Impression scale scores) and safety (adverse events), and the rate of CIILC discontinuation. RESULTS: Significant differences were observed between CAs for several baseline variables: duration of disease progression prior to CIILC onset, off time (34.9-59.7%) and on time (2.6-48.0%; with or without disabling dyskinesia), Hoehn and Yahr score during on time, Unified Parkinson's Disease Rating Scale-III score during both on and off time, presence of≥ 4 motor symptoms, and CIILC dose. Significant differences were observed during follow-up (> 24 months in 9 of the 11 CAs studied) for the percentage of off time and on time without disabling dyskinesia, adverse events frequency, and Clinical Global Impression scores. The rate of CIILC discontinuation was between 20-40% in 9 CAs (78 and 80% in remaining 2 CAs). CONCLUSIONS: This study reveals a marked variability between CAs in terms of patient selection and CIILC safety and effectiveness. These results may have been influenced by patients' baseline characteristics, the availability of multidisciplinary teams, and clinical experience.

PHOTOREFRACTIVE SURGERY WITH EXCIMER LASER AND ITS IMPACT ON THE DIAGNOSIS AND FOLLOW-UP OF GLAUCOMA. A REVIEW.

Excimer laser refractive surgery is a procedure performed worldwide to solve refractive errors and reduce dependence on glasses or contact lenses. There has been an increase in the number of procedures performed around the world. Myopia is the most common indication for corneal photorefractive surgery. Myopic patients have a higher risk of developing some type of glaucoma in their lifetime, such as primary open-angle glaucoma and others. Refractive surgery ablates central corneal stromal tissue, altering its thickness and biomechanics, which in turn makes it difficult to accurately measure intraocular pressure (IOP), since it underestimates it. This underestimation of IOP may delay the diagnosis of de novo glaucoma in patients with a history of refractive surgery. Each patient who wishes to undergo corneal refractive surgery should undergo a thorough glaucoma examination in order to monitor and detect the possible development and / or progression of glaucoma. A very useful practical approach is to perform a series of IOP measurements before and after surgery, when the eye is already stable, and the difference between the averages of the two sets of readings can then be used as a personalised correction factor for postoperative IOP monitoring in that eye. Also, if there is any suspicion of a possible glaucoma, paraclinical tests, such as coherent optical tomography of the retinal nerve fibre layer (RNFL), visual fields and photos of the optic nerve should be requested. All this data prior to refractive surgery should be provided to these patients, so that they can save it and give it to their treating ophthalmologists in the future.

[Intraoperative choledochoscopy usefulness in the treatment of difficult biliary stones]. / Utilidad de la coledocoscopia transquirúrgica en el tratamiento de litos biliares difíciles.

BACKGROUND: Choledocholithiasis presents in 5-10% of the patients with biliary lithiasis. Numerous treatment algorithms have been considered for this disease, however, up to 10% of these therapeutic procedures may fail. Intraoperative choledochoscopy has become a useful tool in the treatment of patients with difficult-to-manage choledocholithiasis. OBJECTIVES: To determine the usefulness of intraoperative choledochoscopy in the laparoendoscopic treatment of difficult stones that was carried out in our service. PATIENTS AND METHODS: A cross-sectional study was conducted. The case records were reviewed of the patients that underwent intraoperative choledochoscopy during biliary tree exploration plus laparoscopic choledochoduodenal anastomosis within the time frame of March 1, 2011 and May 31, 2012, at the Hospital General Dr. Manuel Gea González. Transabdominal choledochoscopies were performed with active stone extraction when necessary, followed by peroral choledochoscopies through the recently formed bilioenteric anastomosis. The data were analyzed with descriptive statistics and measures of central tendency. RESULTS: The mean age was 71 years, 57% of the patients were women, and the ASA III score predominated. Active extraction of stones with 7 to 35mm diameters was carried out in 4 of the cases and the absence of stones in the biliary tract was corroborated in all the patients. The mean surgery duration was 18 minutes (range: 4 to 45min). CONCLUSIONS: Choledochoscopy is a safe and effective minimally invasive procedure for the definitive treatment of difficult stones.

Biparental mitochondrial DNA inheritance in the parasitic trematode Schistosoma mansoni.

The maternal inheritance of mitochondrial DNA (mtDNA) in eukaryotic organisms occurs because of the selective destruction of paternal mtDNA molecules that may be present in the zygote. The elimination of sperm mtDNA is less efficient in interspecific crosses, and biparental inheritance of mtDNA has been observed in a variety of species. Because interspecific crosses are likely to be extremely rare in nature, parental inheritance of mtDNA has been deemed of little relevance to population genetics. The mtDNA of the parasitic trematode Schistosoma mansoni was examined for its utility in addressing epidemiological questions related to the transmission and spread of schistosomiasis. Prior to embarking on such experiments, we sought to confirm the mode of inheritance of this molecule using the highly polymorphic mtDNA minisatellite as a marker. In 3 separate crosses, mtDNA apparently identical to paternal DNA was observed in some individuals of the F2 and F3 generations. These observations thus suggest the intraspecific paternal inheritance of mtDNA across multiple generations in Schistosoma mansoni.

Evaluation of cDNA libraries from different developmental stages of Schistosoma mansoni for production of expressed sequence tags (ESTs).

A comparative study of the gene expression profile in different developmental stages of Schistosoma mansoni has been initiated based on the expressed sequence tag (EST) approach. A total of 1401 ESTs were generated from seven different cDNA libraries constructed from four distinct stages of the parasite life cycle. The libraries were first evaluated for their quality for a large-scale cDNA sequencing program. Most of them were shown to have less than 20% useless clones and more than 50% new genes. The redundancy of each library was also analyzed, showing that one adult worm cDNA library was composed of a small number of highly frequent genes. When comparing ESTs from distinct libraries, we could detect that most genes were present only in a single library, but others were expressed in more than one developmental stage and may represent housekeeping genes in the parasite. When considering only once the genes present in more than one library, a total of 466 unique genes were obtained, corresponding to 427 new S. mansoni genes. From the total of unique genes, 20.2% were identified based on homology with genes from other organisms, 8.3% matched S. mansoni characterized genes and 71.5% represent unknown genes.

HPLC fractionated soluble egg antigen from Schistosoma mansoni elicits a heterogeneous human immune response.

Peripheral blood mononuclear cells (PBMC) from five chronic schistosomiasis patients, three former patients, a SEA sensitized individual, and normal controls were tested in lymphoblastogenesis assays for their ability to proliferate in response to soluble egg antigen (SEA) and soluble worm antigen preparation (SWAP) from Schistosoma mansoni. Cells from all patients and the SEA sensitized individual gave significantly higher responses than the normal controls when stimulated with SEA and SWAP. However, the chronic patients' SEA responses were much lower than those of the former patients and the SEA sensitized individual. When cells from the same donors were tested in the in vitro granuloma assay, all produced significant granulomatous responses except the normal controls. Once it was established that all individuals in the study gave significant lymphoproliferative responses and granulomatous reactions, SEA was subjected to HPLC fractionation to identify immunogenic protein components of SEA. HPLC separation yielded 25 major fractions. SEA responses from the sensitized individual and former patients exhibited broad, unregulated responsiveness including fractions with neutral, less charged proteins while the chronic patients demonstrated a more restricted range of responsiveness. SEA-HPLC fractions 14, 21, and 22 contain the most immunodominant proteins based on cellular proliferation data from reactive individuals tested.

Activated T and B lymphocytes in peripheral blood of patients with Chagas' disease.

Whole blood preparations from patients with either the indeterminate (asymptomatic) or cardiac clinical forms of chronic Trypanosoma cruzi infection were analyzed by flow cytometry using double-labeling to identify subsets of circulating lymphocytes. Several significant differences were demonstrated between the blood lymphocyte profiles of chagasic patients and non-chagasic controls. Clear increase in the percentages and actual numbers of double-positive cells of the phenotype CD3+/HLA-DR+, as well as decrease in the percentage of CD45RA+/CD4+ and CD45RA+/CD8+ T cells, indicate greater numbers of activated T cells circulating in the blood of infected patients. Consistent parallel increases were seen also in the B lymphocyte subset which stained double-positive for CD19/CD5. There were no significant differences in the circulation of these chronic chagasic patients in the CD4:CD8 ratios. Also, no substantive phenotypic differences were observed in the lymphocyte populations between the two ends of the clinical spectrum (indeterminate versus cardiac) in chronic human Chagas' disease. These observations demonstrate that increased levels of activated T cells and CD5+ B cells are present in the circulation of people with chronic Chagas' disease. These are cell phenotypes that have been associated in other conditions with autoimmune, polyclonal, and hyperimmune responses. The specificities of these activated cells and the roles they may play in resistance or pathogenesis during chronic Chagas' disease need now to be determined.

Human schistosomiasis mansoni: studies on in vitro granuloma modulation.

Infection with Schistosoma mansoni induces humoral and T cell mediated responses and leads to a delayed hypersensitivity that results in granulomatous inflammatory disease around the parasite eggs. Regulation of these responses resulting in a reduction in this anti-egg inflammatory disease is apparently determined by idiotypic repertoires of the patient, associated with genetic background and multiple external factors. We have previously reported on idiotype/anti-idiotype-receptor interactions in clinical human schistosomiasis. These findings support a hypothesis that anti-SEA cross-reactive idiotypes develop in some patients during the course of a chronic infection and participate in regulation of anti-SEA cellular immune responses. We report here on experiments which extend those observations to the regulation of granulomatous hypersensitivity measured by an in vitro granuloma model. T cells from chronic intestinal schistosomiasis patients were stimulated in vitro with anti-SEA idiotypes and assayed in an autologous in vitro granuloma assay for modulation of granuloma formation. These anti-SEA idiotype reactive T cells were capable of regulating autologous in vitro granuloma formation. Both CD4 and CD8 T cells could be activated to regulate granuloma formation. This regulatory activity, initiated with stimulatory anti-SEA idiotypic antibodies, was antigenically specific and was dependent on the presence of intact (F(ab')2) immunoglobulin molecules. The ability to elicit this regulatory activity appears to be dose dependent and is more easily demonstrated in chronically infected intestinal patients or SEA sensitized individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

Granulomatous hypersensitivity to Schistosoma mansoni egg antigens in human schistosomiasis. II. In vitro granuloma modulation induced by polyclonal idiotypic antibodies.

We have previously reported on Id/anti-Id-receptor interactions in clinical human schistosomiasis. These findings support a hypothesis that anti-SEA cross-reactive Id develop in some patients during the course of a chronic infection and participate in regulation of anti-SEA cellular immune responses. We report here on experiments that extend those observations to the regulation of granulomatous hypersensitivity measured by an in vitro granuloma model. T cells from chronic intestinal schistosomiasis patients were stimulated in vitro with anti-SEA Id and assayed in an autologous in vitro granuloma assay for modulation of granuloma formation. These anti-SEA Id-reactive T cells were capable of regulating autologous in vitro granuloma formation. Both CD4 and CD8 T cells could be activated to regulate granuloma formation. This regulatory activity, initiated with stimulatory anti-SEA idiotypic antibodies, was antigenically specific and was dependent on the presence of intact F(ab')2 Ig molecules. The ability to elicit this regulatory activity appears to be dose dependent and is more easily demonstrated in chronically infected intestinal patients or SEA-sensitized individuals. These data support the hypothesis that anti-SEA cross-reactive Id are important in regulating granulomatous hypersensitivity in chronic intestinal schistosomiasis patients and these cross-reactive Id appear to play a major role in cell-cell interactions that result in the regulation of anti-SEA cellular immune responses.

Anti-idiotypic T cells in human schistosomiasis.

We have developed an in vitro model of granuloma formation for the purpose of studying the immunological components of granulomatous hypersensitivity in patients infected with S. mansoni. Our previous studies have shown that 1) granulomatous hypersensitivity can be studied by examining the cellular reactivity manifested as multiple cell layers surrounding antigen-conjugated polyacrylamide beads; and 2) this reactivity is a CD4 T cell dependent, macrophage dependent, B cell independent response which is antigenically specific for parasite egg antigens. We report here on idiotype - anti-idiotype receptor interactions involved in the regulation of granulomatous hypersensitivity in patients and former patients infected with S. mansoni. Five human monoclonal antibodies specific for parasite egg antigens were used to activate CD4 and CD8 T cell subsets. These activated anti-idiotypic T cells were then assayed for regulatory effector functions in an autologous in vitro granuloma model.

Immune responses during human schistosomiasis mansoni. XV. Anti-idiotypic T cells can recognize and respond to anti-SEA idiotypes directly.

We previously have shown that former patients and patients with active cases of schistosomiasis mansoni have T lymphocytes in their PBMC that proliferate when exposed to immunoaffinity-purified antibodies against Schistosoma mansoni soluble egg antigens (SEA). These T cell anti-idiotypic responses required the participation of adherent cells, but the role of these cells in the response to the Id has been unclear. We now show that chloroquine does not interfere with Id-elicited stimulation of cells from former patients but completely inhibits their response to the SEA. F(ab')2 fragments of anti-SEA Id are stimulatory, and excess normal human IgG does not alter anti-Id responses. Soluble Id F(ab) fragments are not stimulatory, but rather inhibit stimulation by the intact Id from which they were made. Either intact Id or their F(ab')2 fragments can stimulate non-adherent T cells in the absence of adherent cells if an exogenous source of purified or recombinant human IL-1 is supplied. Nonstimulatory F(ab) fragments can stimulate nonadherent cells if they are bound first to Sepharose 4B and presented in conjunction with IL-1. Thus, T cells from former schistosomiasis patients can react with polyclonal anti-SEA-related Id directly. Under these conditions T cell proliferation requires receptor cross-linking and a source of IL-1 but does not require either "processing" of Id or MHC co-presentation.

Immunoregulation in human schistosomiasis by idiotypic interactions and lymphokine-mediated mechanisms.

Anti-idiotypic (anti-Id) T cells from schistosomiasis patients or former patients proliferate upon exposure to polyclonal or monoclonal anti-soluble egg antigen (SEA) antibodies. Chloroquine does not inhibit, the response, which is induced by F(ab')2 (but not soluble Fab) fragments of these antibodies. Purified T cells from former patients require macrophages or exogenous IL-1 to respond to anti-SEA Ids and can respond to matrix-bound Fab fragments in the presence of IL-1. These anti-Id T cells recognize the Ids directly. Chronic schistosomiasis patients immunoregulate the production of a non-IL-2 lymphokine that stimulates IL-2 receptor expression on resting T cells. This regulation is reversed upon chemotherapeutic cure.

Granulomatous hypersensitivity to Schistosoma mansoni egg antigens in human schistosomiasis. I. Granuloma formation and modulation around polyacrylamide antigen-conjugated beads.

We have developed an in vitro model of granuloma formation for the purpose of studying the immunological components of delayed type hypersensitivity granuloma formation in patients infected with Schistosoma mansoni. Our data show that 1) granulomatous hypersensitivity can be studied by examining the cellular reactivity manifested as multiple cell layers surrounding the antigen conjugated beads; 2) this reactivity is a CD4 cell dependent, macrophage dependent, B cell independent response and 3) the in vitro granuloma response is antigenically specific for parasite egg antigens. Studies designed to investigate the immune regulation of granulomatous hypersensitivity using purified populations of either CD4 or CD8 T cells have demonstrated the complexity of cellular interactions in the suppression of granulomatous hypersensitivity. The anti-S. mansoni egg immune responses of individual patients with chronic intestinal schistosomiasis can be classified either as soluble egg antigen (SEA) hypersensitive with maximal granulomatous hypersensitivity or SEA suppressive with activation of the T cell suppressor pathway with effective SEA granuloma modulation. Our data suggest that T cell network interactions are active in the generation of effective granuloma modulation in chronic intestinal schistosomiasis patients.

Immunoregulation in human Schistosomiasis by idiotypic interactions and lymphokine-mediated mechanisms

Anti-idiotypic (anti-Id) T cells from schistosomiasis patients or former patients proliferate upon exposure to polyclonal or monoclonal anti-soluble egg antigen (SEA) antibodies. Chloroquine does not inhibit, the response, which is induced by F(ab')2 (but not soluble Fab) fragments of these antibodies. Purified T cells from former patients require macrophages or exogenous IL-1 to respond to anti-SEA Ids and can respond to matrix-bound Fab fragments in the presence of IL-1. These anti-Id T cells recognize the Ids directly. Chronic schistosomiasis patients immunoregulate the production of a non-IL-2 lymphokine that stimulates IL-2 receptor expression on resting T cells. This regulation is reversed upon chemotherapeutic cure.

Immune responses during human Schistosomiasis mansoni. Evidence for antiidiotypic T lymphocyte responsiveness.

We present a method for the examination of antiidiotypic cell-mediated reactivity during chronic human infections. Pooled and individual sera from patients with schistosomiasis mansoni were purified on immunoaffinity columns of schistosomal egg antigens (SEA). The eluates contained anti-SEA antibodies, but not SEA. These antibody preparations, and their F(ab)2 fragments, stimulated dose-dependent proliferation of peripheral blood mononuclear cells (PBMN) and T lymphocytes from some, but not all active or former schistosomiasis mansoni patients, and could do so autologously. Stimulation required presentation by plastic-adherent cells. The eluates did not stimulate PBMN from persons who had never had schistosomiasis. Affinity-purified anti-SEA antibodies from former patients (cured for greater than 10 yr) did not stimulate PBMN from patients with active infections. Reabsorption on SEA columns removed stimulatory activity from the eluates. We propose that multiclonal, SEA-related idiotypes expressed by some anti-SEA antibodies stimulate proliferation of T lymphocytes that express antiidiotypic specificities.

Immune responses during human schistosomiasis. XII. Differential responsiveness in patients with hepatosplenic disease.

Thirty-four hospitalized patients and 12 ambulatory patients, all with hepatosplenic schistosomiasis mansoni were evaluated in regard to their peripheral blood mononuclear (PBMN) cell responses to schistosomal antigenic preparations and compared with groups of 40 patients with the hepatointestinal form and 39 patients with the more common, chronic intestinal form of schistosomiasis mansoni. PBMN cell blastogenic responses were measured upon exposure to schistosomal egg antigens (SEA), adult worm antigens (SWAP) and a cercarial antigenic preparation (CERC). All groups had some individuals who did not respond to some or all of these preparations. In the hospitalized hepatosplenic group greater than 50% did not respond to SEA. Analysis of the responses in each group revealed that all responders could be subdivided into moderate and high responders. High responders to SEA had experimental minus control values of greater than 8,000 counts per minute (CPM). For SWAP and CERC, this arbitrary cut-off value was greater than 25,000 CPM and greater than 11,000 CPM, respectively. The percent of high SEA responders in the groups differed considerably. This was 23% in the chronic intestinal group, 40% in the chronic hepatointestinal group, 67% for ambulatory hepatosplenic patients and 20% for hospitalized hepatosplenic patients. Previous studies had demonstrated that 94% of patients with early (2-3 month) acute schistosomiasis mansoni were high responders to SEA and none were nonresponders. Furthermore, at the other end of the spectrum, 100% of former schistosomiasis mansoni patients (treated and cured 7-35 years previously) were high responders to SEA. None were nonresponders to any of the antigen preparations. It is proposed that during acute infection all patients express vigorous responses to SEA. Upon continued infection most patients (75%) modulate this florid response. However, continued high responders comprise 40% of the chronic hepatointestinal cases and almost 70% of the ambulatory hepatosplenic patients. These latter 2 groups may likely represent early forms of the severe clinical disease found in the hospitalized hepatosplenic patient population. Fifty percent of the hospitalized group appear anergic and no longer respond to SEA, while only 20% are high responders. Long after chemotherapy it appears that the anti-SEA regulatory mechanisms of former chronic patients have subsided, leaving strong anti-SEA responsiveness.