Vacunación frente a la encefalitis centroeuropea o la encefalitis transmitida por garrapatas en niños viajeros. Respuesta / No disponible

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Rho/ROCK pathway as a molecular target for modulation of intestinal radiation-induced toxicity.

More than half of cancer patients are treated with radiation therapy. Despite its high therapeutic index, radiation therapy can cause disabling injuries to normal tissues, especially in long-term survivors. Thus, one of the great challenges of modern radiation therapy is to increase tolerance of normal tissue to ionizing radiation in order to improve the quality of life of cancer survivors and/or enhance local control using dose escalation. The physiopathological aspects of normal tissue toxicity have been widely explored; however, none of these descriptive findings has led to the development of effective therapeutic strategies. Several empirical treatments have also been used in clinical trials (superoxide dismutase, pentoxifylline-tocopherol); however, the results are still controversial, and their mechanisms of action have not been clearly defined. The recent development of high-throughput biological approaches will contribute greatly to the characterization of the molecular pathways associated with normal tissue toxicity and the identification of specific and effective molecular targets for therapeutic interventions using already known or new pharmacological compounds. In this paper, we will discuss recent advances made in the characterization of one of the most serious complications of radiation therapy, late intestinal toxicity, using molecular profiling. We will focus on the involvement of the Rho/ROCK pathway in the development and maintenance of late radiation enteropathy. The role of the Rho/ROCK pathway in tissue response to radiation injury will be reviewed, as well as therapeutic perspectives.

Low-resolution mapping of untagged mutations.

The mapping method detailed here is based on the multiplex polymerase chain reaction (PCR) coamplification of 32 molecular markers, using fluorescently labeled oligonucleotides as primers. For the genotyping of a single plant from a mapping population, only two simultaneous amplifications are required, the products of which are finally electrophoresed in an automated DNA sequencer controlled by fragment analysis software. An analysis of the genotypes of 50 plants allows mapping of the mutation of interest within a candidate genomic interval of about 15 cM (3 Mb, corresponding to about 40 BAC clones).

Inhibition of Rho kinase modulates radiation induced fibrogenic phenotype in intestinal smooth muscle cells through alteration of the cytoskeleton and connective tissue growth factor expression.

BACKGROUND: Late radiation enteritis in humans is associated with accumulation of extracellular matrix and increased connective tissue growth factor (CTGF) expression that may involve intestinal muscular layers. AIMS: We investigated the molecular pathways involved in maintenance of radiation induced fibrosis by gene profiling and postulated that alteration of the Rho pathway could be associated with radiation induced fibrogenic signals and CTGF sustained expression. PATIENTS AND METHODS: Ileal biopsies from individuals with and without radiation enteritis were analysed by cDNA array, and primary cultures of intestinal smooth muscle cells were established. Then, the effect of pharmacological inhibition of p160 Rho kinase, using Y-27632, was studied by real time reverse transcription-polymerase chain reaction, western blot, and electrophoretic mobility shift assay. RESULTS: Molecular profile analysis of late radiation enteritis showed alterations in expression of genes coding for the Rho proteins. To investigate further the involvement of the Rho pathway in intestinal radiation induced fibrosis, primary intestinal smooth muscle cells were isolated from radiation enteritis. They retained their fibrogenic differentiation in vitro, exhibited a typical cytoskeletal network, a high constitutive CTGF level, increased collagen secretory capacity, and altered expression of genes coding for the Rho family. Rho kinase blockade induced a simultaneous decrease in the number of actin stress fibres, alpha smooth muscle actin, and heat shock protein 27 levels. It also decreased CTGF levels, probably through nuclear factor kappaB inhibition, and caused decreased expression of the type I collagen gene. CONCLUSION: This study is the first showing involvement of the Rho/Rho kinase pathway in radiation fibrosis and intestinal smooth muscle cell fibrogenic differentiation. It suggests that specific inhibition of Rho kinase may be a promising approach for the development of antifibrotic therapies.

[Impact of a smoke-free workplace policy in a company]. / Impacto de la implantación de una política de trabajo libre de humo en una empresa.

OBJECTIVE: To assess the impact of a smoke-free workplace policy in a company. METHOD: The impact of the implementation of a smoke-free workplace policy was assessed between October 2001 and February 2003 in a company with 184 employees. Two surveys of the entire staff were performed, one before the implementation of the new policy and the other 14 months after. RESULTS: Both passive exposure to tobacco smoke and tobacco consumption among smokers decreased. The proportion of workers free of tobacco smoke exposure at their workplace increased from 32% to 84% (p < 0.001) and, among smokers, the mean daily consumption of cigarettes was reduced by 7.3 cigarettes (p = 0.049). CONCLUSIONS: Demarkation of areas where smoking is allowed not only reduces passive exposure to tobacco smoke at the workplace but also seems to encourage smokers to quit smoking or to reduce tobacco consumption.

[Incidence and characteristics of clinical and sub-clinic hyperthyroidism]. / Incidencia y características del hipertiroidismo clínico y subclínico.

OBJECTIVES: Estimate the incidence of hyperthyroidism in the region of Lleida and compare patients with clinic and subclinic hyperthyroidism. DESIGN: Descriptive retrospective. LOCALIZATION: City of Lleida and the towns of the provinces of Lleida and Huesca. PATIENTS: 190 people diagnosed of hyperthyroidism detected from a sample of 1885 patients with different pathologies, belonging to first visits to de Service of Endocrinology of the Hospital Arnau de Vilanova, during the period from 1999 to 2000. MAIN MEASUREMENTS: The following clinic and demographical variables related to the thyroid pathology were recorded: TSH, T(4), T(3), anti-Tg antibodies, anti-TPO antibodies, age, gender, consumption of salt with iodine and the incidence tax of hyperthyroidism. RESULTS: The incidence tax of hyperthyroidism in the province of Lleida was 46.2 ×10(5) people/year (95% CI, 33.5-61.0). For the 190 patients, the 85% (95% CI, 79.4-90) of them were women; the 38% (95% CI, 31%-45.2%) and the 62% (95% CI, 54.8-69) were diagnosed of clinic and subclinic hyperthyroidism respectively. The subclinic profile was characteristically for had a superior mean of age (P<.003), double of TSH level (P<.03) and half of T(4) level of (P<.001). CONCLUSION: Our study shows a high incidence of hyperthyroidism, and a difference of the two hyperthyroidisms. The detection of this pathology by professionals of primary care can help to improve their therapeutic control.

'In-field' and 'out-of-field' functional impairment during subacute and chronic phases of experimental radiation enteropathy in the rat.

PURPOSE: To investigate subacute and chronic functional consequences of localized irradiation of rat small intestine on exposed and shielded segments (proximal and distal). MATERIALS AND METHODS: The surgical model of a scrotal hernia was used. The ileal loop was exposed to single doses of 18, 21 or 29.6 Gy X-irradiation. Epithelial structure and transport capacity were followed 2 and 26 weeks post-exposure. RESULTS: Irradiated segments showed mucosal ulceration followed by transmural fibrosis. Transport capacity was impaired from 2 to 26 weeks. Subacute functional impairment was noticed in the proximal segment, without either morphological alteration or neutrophil influx. At 26 weeks, both proximal and distal segments showed impaired epithelial transport capacity, with neutrophil influx in the submucosa in cases of 21-Gy exposure and in the submucosa and muscularis propria after 29.6 Gy. CONCLUSIONS: Radiation enteritis was characterized by functional impairment, within as well as outside, the irradiation field. During the subacute phase, the irradiated segment may be a source of mediators which might influence intestinal function outside the site of injury via the blood stream and/or enteric nervous system. The development of an intestinal occlusion syndrome during the chronic phase might be responsible for intestinal dysfunction but it does not rule out a possible inflammatory process developing in the shielded parts of the small intestine.

Abdominal irradiation increases inflammatory cytokine expression and activates NF-kappaB in rat ileal muscularis layer.

The small bowel is an important dose-limiting organ in abdominal radiotherapy because irradiation can cause acute enteritis that, in turn, leads to progressively reduced motility and finally, in a later phase, to fibrosis. Because these clinical symptoms may be caused by the early stage of an inflammatory process, we characterized the radiation-induced intestinal inflammation in rats. Abdominal gamma-irradiation (10-Gy) induced a cascade of inflammatory events characterized by an early (6 h after exposure) increase in IL-1beta, TNF-alpha, and IL-6 mRNA levels in the rat ileal muscularis layer. IL-8 [a cytokine-induced neutrophil chemoattractant (CINC)] mRNA appeared later (at 3 days). The expression of TGF-beta (a profibrotic cytokine) was higher in irradiated than control tissue at day 1, whereas IL-10 (an anti-inflammatory cytokine) expression vanished completely. Despite strong IL-1ra expression, the IL-1ra/IL-1beta ratio, which is an indicator of inflammatory balance, was -41% at day 1 in irradiated compared with control tissue. The nuclear transcription factors NF-kappaB and activator protein-1 (AP-1) govern transcription of these genes, directly or indirectly. Although expression of the subunits of NF-kappaB (p65, p50) and AP-1 (c-fos, c-jun) did not increase, irradiation caused a rapid and persistent translocation of p65 and p50. An imbalance between proinflammatory and anti-inflammatory mediators may contribute to perpetuating intestinal inflammation, thus making it chronic.

Promoter sequences involved in transforming growth factor beta1 gene induction in HaCaT keratinocytes after gamma irradiation.

Transforming growth factor beta 1 (TGFB1) is a cytokine involved in the development of both acute and late cutaneous radiation syndromes. We previously demonstrated that ionizing radiation induces TGFB1 expression in vivo in pig skin within a few hours. The purpose of the present study was to develop an in vitro human model to identify the mechanisms of this early activation. Accordingly, human HaCaT keratinocytes were irradiated with a single dose of 20 Gy. First, radiation-induced TGFB1 overexpression was checked at both the transcriptional and transductional levels in HaCaT cells. Then electrophoretic mobility shift assays (EMSA) and transient transfection with various TGFB1 promoter constructs were used to identify the sequences involved in regulating this promoter. EMSA analysis showed the induction of nuclear protein binding activity by gamma irradiation to the -365 AP1 sequence (TGTCTCA), suggesting the involvement of AP1 sequences in the regulation of TGFB1 transcription. In gene reporter assays, maximal TGFB1 promoter activation was found for the longest construct, which contains two AP1 sequences. However, assays with constructs including deletions showed that these two AP1 sequences were not sufficient to confer TGFB1 inducibility. These results showed for the first time, to our knowledge, that transcriptional regulation is involved in radiation-induced activation of TGFB1 gene expression.

Antifibrotic action of Cu/Zn SOD is mediated by TGF-beta1 repression and phenotypic reversion of myofibroblasts.

Skin fibrosis is characterized by the proliferation and accumulation of activated fibroblasts called myofibroblasts. They exhibit specific cytoskeletal differentiation, overexpress the fibrogenic cytokine TGF-beta1, synthesize excess extracellular matrix compounds and exhibit a depleted antioxidant metabolism. Recently, SOD was successfully used as an antifibrotic agent in vivo, thus challenging the postulate of established fibrosis irreversibility. We postulated that myofibroblasts could be a direct target for this therapeutic effect. To test this hypothesis, we used three-dimensional co-culture models of skin, in which specific phenotypes of normal fibroblasts versus myofibroblasts are retained. These 3-D models were treated with liposomal and carrier-free Cu/Zn SOD, and examined for their effects on cell number, cell death, and phenotypic differentiation. The results show that SOD did not induce myofibroblast cell death, whereas it significantly reduced TGF-beta1 expression, thus demonstrating that SOD might be proposed as a potent antagonist of this major fibrogenic growth factor. We also found that SOD significantly lowered the levels of the myofibroblast marker alpha-sm actin, of beta-actin, and of the extracellular matrix components alpha1(I) collagen and tenascin-C. In conclusion, our results suggest that SOD antifibrotic action occurred in vitro through the reversion of myofibroblasts into normal fibroblasts.

[Radiation-induced superficial fibrosis and TGF-alpha 1]. / Fibrose superficielle radio-induite et TGF-beta 1.

Radiation-induced fibrosis is a late sequela of both therapeutic and accidental irradiations, which has been described in various tissues, including the lung, liver, kidney and skin. This review presents different aspects of superficial radiation-induced fibrosis, such as clinical observations, histological changes, cellular and molecular regulations, and medical management. Recent evidence on the critical role played by TGF-beta 1 in the initiation, development and persistence of fibrosis are discussed, as well as the possibility that this cytokine may constitute a specific target for antifibrotic agents.

The impact of music therapy on language functioning in dementia.

Dementias, such as Alzheimer's disease, include a progressive deterioration of language functioning. While some researchers have reported an increase in patients' self-expression following music therapy, it is not clear whether these changes specifically reflect improved language skills or whether simple interpersonal interaction with a therapist could account for the improvement. In this study, the effects of music therapy were compared to conversational sessions on language functioning in dementia patients. Participants were selected according to the following criteria: (a) residing in a facility specializing in Alzheimer's and related disorders; (b) possessing sufficient verbal ability to answer simple questions and to comply with requests to speak, participate, or sit down; and (c) attaining the written consent of the patient's guardian or representative. All participants had been in music therapy twice per week for at least 3 months prior to the study onset. One week prior to the beginning of the study, subjects were assessed for cognitive functioning using the Mini-Mental State Examination (MMSE), and language ability via the Western Aphasia Battery (WAB). A within-subjects design was used, with order of condition (music or group conversation first) counter-balanced between participants. Subjects participated in groups of 2 to 4, twice per week for 20-30 minutes for a total of 8 sessions (4 music therapy and 4 conversation sessions or vice-versa), and were re-tested on the WAB at the end of each 2 week (4 session) interval. Results from 20 participants revealed that music therapy significantly improved performance on both speech content and fluency dimensions of the spontaneous speech subscale of the WAB (p =.01). While the difference in overall Aphasia Quotient (AQ) for music and conversation sessions (mean AQ = 76 vs. 70, respectively) did not reach statistical significance, data were only available for 10 participants (5 per condition). Hopefully, these findings will stimulate additional research on the use of music therapy interventions with demented patients, as it may offer a noninvasive mechanism to enhance communication between victims and their caregivers.

Music therapy for dementia symptoms.

BACKGROUND: While music/music therapy does not represent a treatment of dementia, its use is based on a possible beneficial effect on symptoms including social, emotional and cognitive skills and for decreasing behavioral problems of individuals with dementias. Thus, there are clear implications for patients' and caregivers' quality of life. However, quantification and documentation of the evidence of this effect is necessary. Professional music therapists are accountable for providing efficient, beneficial treatment. Furthermore, music therapists are responsible for assessing, designing and implementing music therapy treatments, monitoring client progress, and reformulating their practice according to data collected and new advancements in the field. If they wait until sufficient valid, empirical data on all aspects of a disability or music response are available before attempting to design a therapy session, they may well reach retirement age before even one client can be served. On the other hand, promulgating the efficacy of music therapy in general, or of specific music therapy techniques, in the absence of any substantiation other than intuition or tradition borders on professional recklessness. OBJECTIVES: To gather and evaluate the evidence for the effectiveness of music therapy for dementia symptoms. SEARCH STRATEGY: All available sources of references were searched in March 2000 for randomised controlled trials of music therapy used as an intervention in dementia. The search terms included 'controlled trial or study, music, therapy, dementia, Alzheimer's, cognitive impairment' and derivatives of these. SELECTION CRITERIA: The reviewers assessed the methodological quality of the studies available for inclusion. The criteria used are presence and adequacy of a control condition, independent assessment of patients' performance (ie standardized ratings carried out by a person other than the music therapist) and the number of participants (no fewer than three). DATA COLLECTION AND ANALYSIS: No randomised controlled trials, or trials with quantitative data suitable for analysis were found. MAIN RESULTS: The research into music therapy to date has lacked methodological design rigour. However, the research evidence available provides sufficient grounds on which to justify further investigations into the use of music therapy in dementia patients. In this context, the reviewers discuss some of the issues and research from the studies that were considered for inclusion. REVIEWER'S CONCLUSIONS: This review was not able to identify reliable empirical evidence on which to justify the use of music therapy as a treatment for dementia. However, the evidence available suggests that music therapy may be beneficial in treating or managing dementia symptoms, and the predominant conclusion of this review is the highlighting of the need for better designed studies of the intervention.

Music therapy for dementia symptoms.

BACKGROUND: While music/music therapy does not represent a treatment of dementia, its use is based on a possible beneficial effect on symptoms including social, emotional and cognitive skills and for decreasing behavioral problems of individuals with dementias. Thus, there are clear implications for patients' and caregivers' quality of life. However, quantification and documentation of the evidence of this effect is necessary. Professional music therapists are accountable for providing efficient, beneficial treatment. Further, music therapists are responsible for assessing, designing and implementing music therapy treatments, monitoring client progress, and reformulating their practice according to data collected and new advancements in the field. If they wait until sufficient valid, empirical data on all aspects of a disability or music response are available before attempting to design a therapy session, they may well reach retirement age before even one client can be served. On the other hand, promulgating the efficacy of music therapy in general, or of specific music therapy techniques, in the absence of any substantiation other than intuition or tradition borders on professional recklessness. OBJECTIVES: To gather and evaluate the evidence for the effectiveness of music therapy for dementia symptoms. SEARCH STRATEGY: All available sources of references were searched for randomised controlled trials of music therapy used as an intervention in dementia. The search terms included 'controlled trial or study, music*, therapy, dement*, Alzheimer*, cognitive impairment.' SELECTION CRITERIA: The reviewers assessed the methodological quality of the studies available for inclusion. The criteria used are presence and adequacy of a control condition, independent assessment of patients' performance (ie standardized ratings carried out by a person other than the music therapist) and the number of participants (no fewer than three). DATA COLLECTION AND ANALYSIS: No randomised controlled trials, or trials with quantitative data suitable for analysis were found. MAIN RESULTS: The research into music therapy to date has lacked methodological design rigour. However, the research evidence available provides sufficient grounds on which to justify further investigations into the use of music therapy in dementia patients. In this context, the reviewers discuss some of the issues and research from the studies that were considered for inclusion. REVIEWER'S CONCLUSIONS: This review was not able to identify reliable empirical evidence on which to justify the use of music therapy as a treatment for dementia. However, the evidence available suggests that music therapy may be beneficial in treating or managing dementia symptoms, and the predominant conclusion of this review is the highlighting of the need for better designed studies of the intervention.

The effect of music amplitude on the relaxation response.

The purposes of this study were (a) to ascertain how 3 different volume levels of music affect the relaxation response both psychologically (preference scores and self-report) and physiologically (heart rate), (b) to determine the amplitude preference for relaxation among young adults, and (c) to compare differences in preference response between music and nonmusic majors and between the genders. One hundred forty-four college-age music and nonmusic majors were participants in this study. Subjects listened to 27 minutes of music while relaxing. The amplitude of the music was changed every 3 minutes in a randomized order so that each subject received loud (80-90 dB) medium (70-80 dB) or soft (60-70 dB) music 3 times each during the experimental period for a total of 9 amplitude changes. A sample of subjects wore a small heart rate monitor on their wrist and chest during the procedure. Simultaneously with the selected listening, they were encouraged to turn a dial on a Continuous Response Digital Interface (CRDI) indicating their amplitude preference for relaxation. Self-report information was gathered at the beginning and end of the experiment. Results of the CRDI analyses indicate that overall, subjects showed overwhelming preference for the soft music in comparison to medium or loud. Males, however, preferred the loud music more than females, and music majors preferred softer music over non-majors who preferred louder music. There were no differences attributed to amplitude level in the analysis of heart rate data. Analysis of the self report data yielded a wide variety of responses concerning their individual preferences, not always consistent with the empirical measures. Overall, there was an increase in relaxation reported over the duration of the experiment. Response differentiation to loudness levels indicates a long line of useful research not only on relaxation and stress reduction in health related fields, but also on the effects of background amplitude of music while studying, driving, and engaging in other cognitive and motor tasks.

Is Music Therapy an Effective Intervention for Dementia?A Meta-Analytic Review of Literature.

A recent qualitative review of literature in the area of music/ music therapy and dementias published since 1985 suggested that music/music therapy is an effective intervention for maintaining and improving active involvement, social, emotional and cognitive skills, and for decreasing behavioral problems of individuals with dementias (Brotons, Koger, & Pickett-Cooper, 1997). The present analysis sought to update and quantify this relationship, and investigate the extent to which methodological variables influenced treatment effectiveness. Twenty-one empirical studies, with a total of 336 subjects suffering from symptoms of dementia, were included in the meta-analysis. Overall, the effect of music/music therapy was found to be highly significant. A homogeneity analysis determined that the effect sizes were not consistent across studies; thus, a series of moderating variable analyses were conducted. We were unable to determine the source of variability between studies by analyzing type of therapeutic intervention (active or passive), music (live or taped), therapist's training (trained music therapist vs. other professional), dependent variable (behavioral, cognitive, or social), or length of treatment. Although the published literature demonstrates that music/music therapy is an effective method overall for treating symptoms of dementia, systematic variation of treatment protocols is necessary to identify the underlying mechanisms and delineate the most effective techniques.