FDG-PET patterns associated with ideomotor apraxia and imitation apraxia in patients with corticobasal syndrome.

INTRODUCTION: Apraxia is a core clinical feature of corticobasal syndrome (CBS). Among the subtypes of apraxia, ideomotor and imitation apraxia are frequently found in CBS. However, little is known about the brain networks that are characteristic of each apraxia subtype or their clinical implication. In this study, we used 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) to explore the specific patterns of glucose hypometabolism that are characteristic of apraxia subtypes by focusing on ideomotor and imitation apraxia. METHODS: We compared the areas of glucose hypometabolism in the brains of 52 patients with CBS and 13 healthy controls, both as a whole and according to apraxia subtypes. In addition, we investigated the relationship between the apraxia subtypes and the clinical phenotype of CBS. RESULTS: In patients with CBS, common hypometabolism was observed in the frontal gyrus, precentral gyrus and caudate regardless of apraxia subtypes. In particular, ideomotor apraxia was associated with hypometabolism in the angular gyrus, while imitation apraxia was associated with hypometabolism in the posterior part including the postcentral gyrus, precuneus, and posterior cingulate gyrus. Patients who showed both ideomotor and imitation apraxia were more likely to show the typical features of CBS and progressive supranuclear palsy compared with patients showing only one type of apraxia. CONCLUSION: Group comparison analysis using FDG-PET revealed distinct pathways of ideomotor and imitation apraxia in CBS. These findings add to our understanding of the brain networks underlying apraxia in association with the clinical features of CBS.

Cortical hypometabolism associated with cognitive impairment of multiple system atrophy.

INTRODUCTION: Cognitive impairment is not uncommon in patients with multiple system atrophy (MSA). This study investigated the cortical metabolic changes of MSA and the cortical structure associated with cognitive impairment. METHODS: The study included probable/definite MSA patients who underwent fluorodeoxyglucose positron emission tomography and cognitive evaluation based on mini-mental status examination (MMSE). Cerebral metabolism of the entire MSA patients (n = 88) was compared with healthy controls (n = 19) by voxel-wise statistical parametric mapping. Eight brain regions of interest (ROIs) were selected accordingly: the dorsolateral prefrontal, medial superior frontal, insular, posterior parietal, precuneus, lateral temporal, medial temporal, and posterior cingulate regions. Using validated population-based norms, MSA patients were divided by MMSE z-scores into MSA with cognitive dysfunction (MSA-D, n = 30) and without cognitive dysfunction (MSA-ND, n = 58). Regional metabolism of the selected ROIs was compared between the MSA-D and MSA-ND groups by logistic regression models. Correlations between the regional metabolism of the selected ROIs and MMSE z-scores were analyzed with a linear regression model. RESULTS: Voxel-wise analysis showed hypometabolism in the frontal, temporal, parietal, and limbic areas in MSA patients than in controls. ROI-based comparisons showed that metabolism in the posterior cingulate (P = 0.006) and medial temporal (P = 0.039) regions was significantly lower in the MSA-D than in the MSA-ND group. The degree of posterior cingulate metabolism correlated significantly with MMSE z-score (P = 0.023). CONCLUSIONS: MSA shows fronto-temporo-parietal cortical involvement. Hypometabolism of the limbic regions is associated with cognitive impairment in MSA.

Cognitive profile as a predictor of the long-term outcome after deep brain stimulation in Parkinson's disease.

BACKGROUND: Although dementia is a contraindication for deep brain stimulation (DBS) in patients with Parkinson's disease (PD), the concept is supported by little scientific evidence. Moreover, it is unclear whether PD with mild cognitive impairment (PD-MCI) or domain-specific cognitive impairments affect the outcome of DBS in non-demented PD patients. OBJECTIVE: To investigate the influence of baseline cognitive profiles of PD on the outcome of DBS. METHODS: Baseline cognitive levels of patients with PD who underwent DBS were classified into PD with dementia (PDD) (n = 15), PD-MCI (n = 210), and normal cognition (PD-NC) (n = 79). The impact of the cognitive level on key DBS outcome measures [mortality, nursing home admission, progression to Hoehn&Yahr (HY) stage 5 and progression to PDD] were analyzed using Cox regression models. We also investigated whether impairment of a specific cognitive domain could predict these outcomes in non-demented patients. RESULTS: Patients with PDD showed a substantially higher risk of nursing home admission and progression to HY stage 5 compared with patients with PD-MCI [hazard ratio (HR) 4.20, P = .002; HR = 5.29, P < .001] and PD-NC (HR 7.50, P < .001; HR = 7.93, P < .001). MCI did not alter the prognosis in patients without dementia, but those with visuospatial impairment showed poorer outcomes for nursing home admission (P = .015), progression to HY stage 5 (P = .027) and PDD (P = .006). CONCLUSIONS: Cognitive profiles may stratify the pre-operative risk and predict long-term outcomes of DBS in PD.

Post-Pump Chorea and Progressive Supranuclear Palsy-Like Syndrome Following Major Cardiac Surgery.

BACKGROUND: Post-pump chorea and progressive-supranuclear palsy (PSP)-like syndrome after aortic surgery are 2 distinct movement disorders following major cardiac surgeries. CASES: We herein report 3 patients with movement disorders that developed after major cardiac surgeries. Two patients developed post-pump chorea after pulmonary endarterectomy, and 1 further case developed PSP-like syndrome after aortic replacement surgery. The 2 conditions share several common aspects. Both are preceded by surgeries that undergo cardiopulmonary bypass and deep hypothermia circulatory arrest procedures. Most cases present with biphasic course. However, post-pump chorea occurs in all age populations after any surgeries that undergo deep hypothermia circulatory arrest, whereas PSP-like syndrome is reported exclusively in the adult population after aortic surgery. CONCLUSIONS: Post-pump chorea and PSP-like syndrome are neurologic complications of major cardiac surgeries that should not be underrecognized. Further reports to establish their common pathogenic mechanism should be encouraged.

Uneven age effects of [(18)F]FP-CIT binding in the striatum of Parkinson's disease.

OBJECTIVE: Dopamine transporter (DAT) imaging shows age-related decline of ligand binding in the normal striatum, a decline attributed to regulatory changes. We investigated if similar changes occur in the striatum of Parkinson's disease (PD) patients, using PET and [(18)F]FP-CIT, a ligand for DAT. METHODS: We performed [(18)F]FP-CIT PET in 39 drug-naïve, de novo PD patients (age 56.0 ± 11.6 years, mean ± SD) and 34 healthy control subjects (age 52.3 ± 17.8). Parkinsonism was assessed by UPDRS III and Purdue pegboard. Binding ratios of [(18)F]FP-CIT were obtained in the putamen and caudate using the occipital cortex as reference. RESULTS: Mean [(18)F]FP-CIT binding ratios in PD were 3.76 ± 0.74 (mean ± SD) in the putamen and 6.80 ± 1.05 in the caudate nucleus, significantly smaller than those in the healthy control (9.20 ± 1.38, 8.66 ± 1.12, respectively; p < 0.001 vs. healthy control for both). Regression analysis of [(18)F]FP-CIT binding ratios on age in healthy subjects showed significant correlations in the putamen (p < 0.001) and caudate nucleus (p < 0.001). Similar analysis in PD patients also showed significant correlations in the putamen (p = 0.015) and caudate nucleus (p = 0.018). The slope of regression in the putamen was -0.061 in the healthy control and -0.017 in PD, with significant differences between the two groups (p = 0.0003). In contrast, the regression slope in the caudate nucleus was -0.040 in the healthy control group, and -0.032 in the PD group with no significant differences between the two groups. CONCLUSIONS: Striatal [(18)F]FP-CIT binding showed significant age affects in patients with de novo PD after standardization for the severity of disease. The age effects were significantly smaller in PD patients than those in healthy subjects, but only in the putamen, not in the caudate nucleus. Given that age-related attrition of DA neurons is even in normal striatum, the uneven age effects in the parkinsonian striatum are likely to reflect the superimposition of disease-driven compensation on the aging effect.

Expansion of the clinicopathological and mutational spectrum of Perry syndrome.

BACKGROUND: Perry syndrome (PS) caused by DCTN1 gene mutation is clinically characterized by autosomal dominant parkinsonism, depression, severe weight loss, and hypoventilation. Previous pathological studies have reported relative sparing of the cerebral cortex in this syndrome. Here, we characterize novel clinical and neuroimaging features in 3 patients with PS. METHODS: (18)F-fluorinated N-3-fluoropropyl-2-ß-carboxymethoxy-3-ß-(4-iodophenyl) nortropane ([(18)F]FP-CIT) PET, [(18)F]fluorodeoxyglucose PET, or volumetric MRI was performed in probands, and imaging data were analyzed and compared with those of control subjects. RESULTS: We identified 2 novel mutations of DCTN1. Oculogyric crisis that presented before levodopa treatment was observed in 1 case. One patient had supranuclear gaze palsy. In 2 cases, [(18)F]FP-CIT showed marked loss of dopamine transporter binding with only mild parkinsonism. Areas of hypometabolism or cortical thickness change were observed in dorsolateral frontal, anterior cingulate, lateral temporal, and inferior parietal cortices. CONCLUSION: Oculomotor manifestations are not uncommon in PS. Neuroimaging studies suggest involvement of the frontotemporoparietal cortex, which may be the clinical correlate of apathy and depression, as well as pathological changes in subcortical structures.

Age-specific progression of nigrostriatal dysfunction in Parkinson's disease.

OBJECTIVE: To investigate in vivo the impact of age on nigrostriatal dopamine dysfunction in Parkinson's disease (PD). METHODS: PD patients (n = 78) and healthy control subjects (n = 35) underwent longitudinal positron emission tomography assessments using 3 presynaptic dopamine markers: (1) [¹¹C](±)dihydrotetrabenazine (DTBZ), to estimate the density of the vesicular monoamine transporter type 2; (2) [¹¹C]d-threo-methylphenidate, to estimate the density of the plasma membrane dopamine transporter; and (3) 6-[¹8F]-fluoro-L-dopa, to estimate the activity of the enzyme dopa-decarboxylase. RESULTS: The study comprised 438 PD scans and 241 control scans (679 scans in total). At symptom onset, the loss of putamen DTBZ binding was substantially greater in younger compared to older PD patients (p = 0.015). Remarkably, however, the rate of progression of DTBZ binding loss was significantly slower in younger patients (p < 0.05). The estimated presymptomatic phase of the disease spanned more than 2 decades in younger patients, compared to 1 decade in older patients. INTERPRETATION: Our results suggest that, compared to older patients, younger PD patients progress more slowly and are able to endure more damage to the dopaminergic system before the first motor symptoms appear. These observations suggest that younger PD patients have more efficient compensatory mechanisms.

Epidermoid cancer of the anal canal.

Anal canal cancer is a rare cancer with incidence that continues to rise. This has been in large part due to increased prevalence of immunosuppressed conditions such as organ transplantation and human immunodeficiency virus along with transmission of the human papillomavirus. Identification of high-risk groups and close monitoring of these groups can help to detect earlier stages of cancer. Chemoradiation therapy remains the mainstay of treatment with excellent outcomes. Surgery for anal canal carcinoma remains as a salvage technique for failed chemoradiation or recurrent disease.

Longitudinal progression of sporadic Parkinson's disease: a multi-tracer positron emission tomography study.

Parkinson's disease is a heterogeneous disorder with multiple factors contributing to disease initiation and progression. Using serial, multi-tracer positron emission tomography imaging, we studied a cohort of 78 subjects with sporadic Parkinson's disease to understand the disease course better. Subjects were scanned with radiotracers of presynaptic dopaminergic integrity at baseline and again after 4 and 8 years of follow-up. Non-linear multivariate regression analyses, using random effects, of the form BP(ND)(t) or K(occ)(t) = a*e((-)(bt)(-d)(A) + c, where BP(ND) = tracer binding potential (nondispaceable), K(OCC) = tracer uptake constant a, b, c and d are regression parameters, t is the symptom duration and A is the age at onset, were utilized to model the longitudinal progression of radiotracer binding/uptake. We found that the initial tracer binding/uptake was significantly different in anterior versus posterior striatal subregions, indicating that the degree of denervation at disease onset was different between regions. However, the relative rate of decline in tracer binding/uptake was similar between the striatal subregions. While an antero-posterior gradient of severity was maintained for dopamine synthesis, storage and reuptake, the asymmetry between the more and less affected striatum became less prominent over the disease course. Our study suggests that the mechanisms underlying Parkinson's disease initiation and progression are probably different. Whereas factors responsible for disease initiation affect striatal subregions differently, those factors contributing to disease progression affect all striatal subregions to a similar degree and may therefore reflect non-specific mechanisms such as oxidative stress, inflammation or excitotoxicity.

Brain transplantation of human neural stem cells transduced with tyrosine hydroxylase and GTP cyclohydrolase 1 provides functional improvement in animal models of Parkinson disease.

Parkinson disease is a neurodegenerative disease characterized by loss of midbrain dopaminergic neurons resulting in movement disorder. Neural stem cells (NSC) of the CNS have recently aroused a great deal of interest, not only because of their importance in basic research of neural development, but also for their therapeutic potential in neurological disorders. We have recently generated an immortalized human NSC cell line, HB1.F3, via retrovirus-mediated v-myc transfer. This line is capable of self-renewal, is multipotent, and expresses cell specific markers for NSC, ATP-binding cassettes transporter (ABCG2) and nestin. Next, we co-transduced the F3 NSC line with genes encoding tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GTPCH1) in order to generate dopamine-producing NSC. The F3.TH.GTPCH human NSC line expresses TH and GTPCH phenotypes as determined by RT-PCR, western blotting and immunocytochemistry, and shows a 800 to 2000-fold increase in production of L-dihydroxyphenyl alanine in HPLC analysis. A marked improvement in amphetamine-induced turning behavior was observed in parkinsonian rats implanted with F3.TH.GTPCH cells, but not in control rats receiving F3 NSC. In the animals showing functional improvement, a large number of TH-positive F3.TH.GTPCH NSC were found at injection sites. These results indicate that human NSC, genetically transduced with TH and GTPCH1 genes, have great potential in clinical utility for cell replacement therapy in patients suffering from Parkinson disease.

PET in LRRK2 mutations: comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation.

Parkinson's disease may arise from multiple aetiologies, including genetic mutations that are for the most part uncommon. We describe here the positron emission tomography (PET) findings in clinically affected and asymptomatic, high-risk members of two autosomal dominantly inherited Parkinson's disease kindreds with recently described mutations at the PARK8 locus, in a novel gene encoding a leucine-rich repeat kinase (LRRK2). Affected family members have L-dopa-responsive parkinsonism with loss of dopaminergic nigral neurons and pleomorphic subcellular pathology. Fifteen family members underwent PET using: 18F-6-fluoro-L-dopa (18F-dopa) to assess dopamine (DA) synthesis and storage, 11C-(+/-)-dihydrotetrabenazine (11C-DTBZ) for the vesicular monoamine transporter, and 11C-d-threo-methylphenidate (11C-MP) for the membrane dopamine transporter (DAT). Measurements were compared with normal (n = 33) and sporadic Parkinson's disease (sPD) (n = 67) control groups. Four clinically affected members had findings similar to sPD, with impaired presynaptic DA function affecting the putamen more than the caudate. In two affected members, D2 dopamine receptor binding was intact. Two asymptomatic mutation carriers had abnormal DAT binding with another two developing such abnormalities over 4 years of follow-up. In these individuals, 18F-dopa uptake remained normal, although two of them also displayed abnormal 11C-DTBZ binding. Our study demonstrates that the in vivo neurochemical phenotype of LRRK2 mutations is indistinguishable from that of sPD, despite the pathological heterogeneity of the condition. Furthermore, we suggest that compensatory changes including downregulation of the DAT and upregulation of decarboxylase activity may delay the onset of parkinsonian symptoms.

Lack of regional selectivity during the progression of Parkinson disease: implications for pathogenesis.

BACKGROUND: Dopamine terminal loss in the putamen of patients with Parkinson disease (PD) shows a regional heterogeneity, reflecting selective vulnerability of degenerating neurons to mechanisms of cell death. HYPOTHESIS: If the same pathogenic mechanisms are responsible for the onset and progression of PD, the regional selectivity of dopamine cell loss will be the same throughout the course of the disorder. OBJECTIVE: To investigate the regional selectivity of dopamine terminal loss during the progression of PD. PARTICIPANTS: We studied 67 patients with PD and 20 healthy subjects using positron emission tomography with [(11)C](+/-)dihydrotetrabenazine (DTBZ). RESULTS: Regional values of DTBZ binding potential (calculated as maximum specific binding [B(max)] divided by the equilibrium dissociation constant K(d)) against disease duration in the putamen of PD patients were best described by a multivariate exponential model with distinct parallel asymptotic values that were significantly (P<.001) different across 4 regions of the putamen. The extent of loss of DTBZ binding potential with disease progression during the clinical stage of PD (early vs late PD) was similar between the anterior (-33%, using early PD as the baseline) and posterior (-29%) putamen. In contrast, the extent of loss of DTBZ binding potential in early PD, which reflects the cumulated loss of DTBZ binding potential from the onset of the disorder (in healthy subjects vs those with early PD), was significantly (P<.001) lower in the posterior (-58%, using healthy subjects as the baseline) than the anterior (-42%) putamen. CONCLUSION: To the extent that DTBZ positron emission tomography provides an accurate estimate of loss of dopamine neurons, our findings suggest that the mechanisms responsible for the progression of PD may not be the same as those responsible for its onset.

[11C]DTBZ-PET correlates of levodopa responses in asymmetric Parkinson's disease.

Levodopa effectively improves motor symptoms of Parkinson's disease. However, the beneficial effects of levodopa often erode over time with the emergence of response fluctuations. Although these response changes have been recognized from the early levodopa era, their mechanisms remain poorly understood. We investigated the role of dopamine (DA) terminal loss in the development of motor fluctuations by employing PET with [11C](+/-)dihydrotetrabenazine ([11C]DTBZ) as an in vivo marker for DA nerve terminals. Levodopa response was characterized by analysing the time-response curve to a single dose of levodopa with a finger-tapping test. PET scans were performed in 11 patients with asymmetric Parkinson's disease (age: 61.12 +/- 7.97 years; duration of Parkinson's disease: 10.55 +/- 4.53 years; mean +/- SD). Each patient performed finger-tapping tests for up to 5 h after taking a therapeutic dose of levodopa. Results showed significantly lower [11C]DTBZ binding potential (BP; Bmax/Kd) and baseline tapping rates on the more affected putamen and corresponding body side, respectively, than on the other (P = 0.003 for the former, P = 0.013 for the latter). Among the variables describing the time-response curve, the duration and early decay time were significantly shorter on the more affected side (P = 0.051 and P = 0.021, respectively). Latency to the onset and latency to 50% Emax (the magnitude of the levodopa response) were significantly longer on the more-affected side (P = 0.013 and P = 0.004, respectively). Emax was not significantly different between the two sides. The asymmetry (difference from the more affected to less affected side) of [11C]DTBZ BP in the putamen showed a highly significant correlation with the corresponding asymmetry of the estimated EC50 (levodopa concentration producing 50% of the maximal response; P = 0.022; r = -0.727), a marginally significant correlation with that of latency to the onset (P = 0.065; r = -0.583) and no significant correlation with that of the magnitude, duration or early decay time. This pattern of changes in levodopa response from the less affected to more affected side was similar to that from stable to fluctuating responders except for the latency to onset. These findings suggest a pathogenetic role for DA terminal loss in the development of motor fluctuations. However, the absence of a significant correlation between the early decay of levodopa response and DA terminal density suggests that DA terminal loss alone cannot account for the development of motor fluctuations. Therefore, our study suggests that both levodopa treatment and DA terminal loss contribute to the pathogenesis of motor fluctuations.

VMAT2 binding is elevated in dopa-responsive dystonia: visualizing empty vesicles by PET.

Dopa-responsive dystonia (DRD) is a lifelong disorder in which dopamine deficiency is not associated with neuronal loss and therefore it is an ideal human model for investigating the compensatory changes that occur in response to this biochemical abnormality. Using positron emission tomography (PET), we examined the (+/-)-alpha-[(11)C]dihydrotetrabenazine ([(11)C]DTBZ) binding potential of untreated DRD patients and normal controls. Two other PET markers of presynaptic nigrostriatal function, d-threo-[(11)C]methylphenidate ([(11)C]MP) and 6-[(18)F]fluoro-L-dopa ([(18)F]-dopa), and [(11)C]raclopride were also used in the study. We found increased [(11)C]DTBZ binding potential in the striatum of DRD patients. By contrast, no significant changes were detected in either [(11)C]MP binding potential or [(18)F]-dopa uptake rate constant. In addition, we found evidence for increased dopamine turnover in one DRD patient by examining changes in [(11)C]raclopride binding potential in relation to levodopa treatment. We propose that the increase in [(11)C]DTBZ binding likely reflects the dramatic decrease in the intravesicular concentration of dopamine that occurs in DRD; upregulation of vesicular monoamine transporter type 2 (VMAT2) expression may also contribute. Our findings suggest that the striatal expression of VMAT2 (as estimated by [(11)C]DTBZ binding) is not coregulated with dopamine synthesis. This is in keeping with a role for VMAT2 in other cellular processes (i.e., sequestration and release from the cell of potential toxic products), in addition to its importance for the quantal release of monoamines.

Age and severity of nigrostriatal damage at onset of Parkinson's disease.

The clinical evolution of Parkinson's disease (PD) is known to be partly dependent on the age of onset. For example, motor complications associated with chronic dopaminomimetic treatment occur more often in younger patients. However, few attempts have been made to characterize the functional pathological differences underlying this age effect. We investigated the relationship between age and severity of nigrostriatal damage at onset of PD. Twenty patients with early PD (symptom duration

The role of endoscopic colon surveillance in the transplant population.

PURPOSE: Long-term immunosuppression increases the risks of developing certain malignancies. This study examines the effects of long-term immunosuppression on the development of metachronous adenomatous polyps and attempts to formulate a sound surveillance plan for these individuals. METHOD: A retrospective analysis was performed of all solid organ transplant patients at Henry Ford Hospital from 1989 to 1999, with a specific focus on endoscopic evaluation and outcomes after three years of surveillance. Comparison was made to an age-matched and gender-matched control group from the same endoscopic database. Variables were compared using the chi-squared test, Fisher's exact probability test, and Hochberg's test. RESULTS: A total of 992 solid organ transplants were performed. Two hundred twenty-nine (23 percent) of the transplant recipients underwent pretransplant colonoscopy, of which 178 patients (78 percent) were age 50 years or older. Seventy-four (32 percent) of the prescreened population had polyps, of which 45 patients (61 percent) had adenomas. Twenty-seven patients (36 percent) had synchronous polyps, of which 12 patients (16 percent) had synchronous adenomas. At 3-year follow-up 59 patients (80 percent) had metachronous polyps. Twenty-eight patients (38 percent) had metachronous adenomas. Eleven patients (15 percent) with hyperplastic polyps on initial colonoscopy developed adenomas. The control group consisted of 25 females and 50 males with a mean age of 65.5 +/- 1.1 years. Fifty-one patients (68 percent) had adenomas on endoscopy. Twenty-four patients (32 percent) had synchronous lesions, of which 13 patients (17 percent) had synchronous adenomas. Sixty-one patients (84 percent) developed metachronous lesions, of which 33 patients (43 percent) had metachronous adenomas at 3 years. There was no difference in the polyp size or histology between the two groups. There was no statistically significant difference between the transplant patients and the control group in all analyses. CONCLUSION: Because of an equivalent incidence of adenomatous polyps compared with the general population, current screening criteria should be used in patients posttransplant. Transplant patients are not more likely to develop metachronous polyps than the general population. Therefore, posttransplant polyp surveillance should not be more frequent than currently recommended for nontransplant patients with adenomatous polyps.

Síndrome de Kallmann: reporte de un embarazo y revisión de la literatura / Kallmann syndrome: report of a pregnancy and literature review

Reportamos el caso de un embarazo en una paciente con síndrome de kallmmann. La paciente respondió adecuadamente a pruebas de estimulación con hormona liberadora de gonadotropians (GnRH) y posterior al tercer ciclo de estimulación, la paciente se hizo refractaria al tratamiento. La paciente no tuvo respuesta a terapia con hormona folículo-estimulante (FSH) ni a gpmpdptrpómas de mujer menopáusica (hMG) para inducción de la ovulación. Por éstas razones, usamos una terapia breve con acetato de leuprolide (LUPRON) seguido por hMG, lo cual resultó en ovulación y un subsecuente embarazo, mismo que se llevó a término. Presentamos de ésta manera un manejo alterno para inducción de la ovulación en pacientes con el síndrome de kallmann y una revisión de la literatura.