Evaluation of the Feasibility, Safety and Efficacy of the Use of Intravenous Infusions of Adenosine Triphosphate (ATP) in People Affected by Moderate to Severe Alzheimer's Disease: A Double-Blind Masked Clinical Trial for Dose Finding.

BACKGROUND: There are currently no drug therapies modifying the natural history of patients suffering Alzheimer's disease (AD). Most recent clinical trials in the field include only subjects in early stage of the disease, while patients with advanced AD are usually not represented. OBJECTIVES: To evaluate the feasibility, safety and efficacy of systemic infusions of adenosine triphosphate (ATP) in patients with moderate to severe AD, and to select the minimum effective dose of infusion. DESIGN: A phase IIb, randomized, double-blind, placebo-controlled clinical trial investigates. PARTICIPANTS: A total of 20 subjects with moderate or severe AD were included, 16 in the treatment group and 4 in the placebo group (4:1 randomization) at two dosage regimens, 6-hour or 24-hour infusions. RESULTS: The proof-of-concept study was successfully conducted, with no significant deviations from the study protocol and no serious adverse events reported. Regarding efficacy, only marginal differences were observed between ATP and placebo arms for H-MRS and MMSE variables. CONCLUSIONS: Our study demonstrates that the use of ATP infusion as therapy is feasible and safe. Larger studies are however needed to assess the efficacy of ATP in moderate to severe AD.

Endoftalmitis endógena bilateral por Candida glabrata posterior a cirugía bariátrica complicada / Bilateral endogenous ophthalmitis due to Candida glabrata after complicated bariatric surgery

CASO CLÍNICO: Mujer de 43 años presenta disminución de agudeza visual en ojo derecho. En la evaluación, se encuentran lesiones retinianas «en bolas de nieve» en ambos ojos. En ausencia de mejoría con tratamiento empírico antifúngico intravítreo, se realiza cultivo de vítreo y se halla Candida glabrata. La paciente recibe anfotericina B intravítrea y tratamiento sistémico con caspofungina y anfotericina B complejo lipídico. Discusión: La endoftalmitis endógena fúngica es una afección ocular grave. Existen escasos artículos de endoftalmitis endógena por Candida glabrata. Los regímenes de tratamiento para endoftalmitis por Candida incluyen combinaciones de antifúngicos sistémicos o intravítreos, así como vitrectomía

CASE REPORT: A 43 year-old female presented with decreased visual acuity in the right eye. «Snowball-like» retinal lesions were found in both eyes on examination. Due to a lack of improvement with intravitreal antifungal empirical treatment, vitreous culture was performed and Candida glabrata was isolated. The patient then received intravitreal amphotericin B, as well as systemic treatment with caspofungin and amphotericin B lipid complex. DISCUSSION: Endogenous fungal endophthalmitis is a sight-threatening condition. There are few reports of Candida glabrata endogenous endophthalmitis. Treatment regimens for Candida endophthalmitis include combinations of systemic and/or intravitreal antifungals, as well as vitrectomy

[Bilateral endogenous ophthalmitis due to Candida glabrata after complicated bariatric surgery]. / Endoftalmitis endógena bilateral por Candida glabrata posterior a cirugía bariátrica complicada.

CASE REPORT: A 43 year-old female presented with decreased visual acuity in the right eye. «Snowball-like¼ retinal lesions were found in both eyes on examination. Due to a lack of improvement with intravitreal antifungal empirical treatment, vitreous culture was performed and Candida glabrata was isolated. The patient then received intravitreal amphotericin B, as well as systemic treatment with caspofungin and amphotericin B lipid complex. DISCUSSION: Endogenous fungal endophthalmitis is a sight-threatening condition. There are few reports of Candida glabrata endogenous endophthalmitis. Treatment regimens for Candida endophthalmitis include combinations of systemic and/or intravitreal antifungals, as well as vitrectomy.

Wnt signaling and hepatocarcinogenesis: the hepatoblastoma model.

The Wnt/ß-catenin pathway plays a key role in liver development, regeneration and tumorigenesis. Among human cancers tightly linked to abnormal Wnt/ß-catenin signaling, hepatoblastoma (HB) presents with the highest rate (50-90%) of ß-catenin mutations. HB is the most common malignant tumor of the liver in childhood. This embryonic tumor differs from hepatocellular carcinoma by the absence of viral etiology and underlying liver disease, and by distinctive morphological patterns evoking hepatoblasts, the bipotent precursors of hepatocytes and cholangiocytes. Recent studies of the molecular pathogenesis of hepatoblastoma have led to identify two major tumor subclasses resembling early and late phases of prenatal liver development and presenting distinctive chromosomal alterations. It has been shown that the molecular signature of Wnt/ß-catenin signaling in hepatoblastoma is mainly imposed by liver context, but differs according to developmental stage. Finally, the differentiation stage of tumor cells strongly influences their invasive and metastatic properties, therefore affecting clinical behavior.

Molecular biology of the hepatitis B virus and role of the X gene.

The hepatitis B virus (HBV) is a widespread human pathogen and a major health problem in many countries. Molecular cloning and sequencing of the viral DNA genome has demonstrated a small and compact structure organized into four overlapping reading frames that encode the viral proteins. Besides structural proteins of the core and the envelope, HBV encodes a DNA polymerase with reverse transcriptase activity, a secreted antigen of unknown function, and a transcriptional activator that is essential for viral replication. Major steps of the viral life cycle have been unraveled, including transcription of all viral RNAs from nuclear covalently closed circular DNA (cccDNA), followed by encapsidation of pregenomic RNA, a more-than-genome length transcript, and reverse transcription of pregenomic RNA leading to asymmetric synthesis of the DNA strands. Although HBV has been recognized as a human tumor virus, no direct transforming activity could be evidenced in different cellular and animal models. However, the transcriptional regulatory protein HBx encoded by the X gene is endowed with weak oncogenic activity. HBx harbors pleiotropic activities and plays a major role in HBV pathogenesis and in liver carcinogenesis.

[Fundamental and translational research on hepatocellular carcinoma in 2008: forces and priorities]. / Recherche fondamentale et translationnelle sur le carcinome hépatocellulaire en 2008 : avancées récentes et perspectives.

Hepatocellular carcinogenesis is usually the result of a muti-step process. It begins with an exposure to various risk factors; followed by the development of a chronic hepatitis and cirrhosis that is a pre-neoplastic step; and finally after the occurrence of an hepatocellular carcinoma (HCC), different molecular events control aggressiveness of the tumors. The aim of this work was to identify in the international context, forces and priorities of the fundamental and translational HCC research.

Utilidad de las baterías neuropsicológicas estandarizadas en sujetos adultos con síndrome de Down y demencia / The Usefulness of standard neuropsychological testing for adults with Down syndrome and dementia

(SD) tienen un riesgo aumentado de desarrollar la enfermedad de Alzheimer (EA). Puesto que en el SD se parte de un nivel intelectual menor que en la población general, a veces resulta difícil objetivar si existe o no, en el envejecimiento, una reducción de sus capacidades para cumplir los criterios diagnósticos de EA. El «Mini-MentalState Examination» (MMSE) y el «Severe ImpairmentBattery» (SIB) son pruebas cognitivas estandarizadas ampliamente utilizadas para detectar demencia en la población general. Escasos estudios han utilizado el MMSE y la SIB en sujetos con SD con sospecha de demencia. El objetivo del presente estudio consistió en analizar la utilidad del MMSE y la SIB en la valoración de las funciones cognitivas de sujetos con SD. Método: Se administró el MMSE y la SIB a 45 sujetos con SD (16 con EA y 29 sin demencia) y el cuestionario «Dementia Questionnaire for Mentally Retarded Persons» (DMR) a sus cuidadores. Resultados: Los sujetos con SD y demencia mostraron una mayor alteración que los sujetos con SD sin demencia en la DMR-social y DMR-total, pero no se hallaron diferencias significativas entre ambos grupos en el rendimiento de la SIB, MMSE ni DMR-cognitivo. Las puntuaciones en la SIB correlacionaron significativamente con las del MMSE, DMR-total, DMR-cognitivo y DMR-social. El rendimiento en el MMSE correlacionó significativamente con el del DMR-total, DMR-cognitivo y SIB. Conclusiones: El MMSE y la SIB son herramientas útiles para el seguimiento de las funciones cognitivas en sujetos con SD y deterioro cognitivo o demencia (AU)

Background: Subjects with Down syndrome (DS) have an increased risk of Alzheimer’s disease (AD). As intellectual ability is lower in DS subjects than among the general population, it is difficult to determine whether cognition has deteriorated with age to the point of fulfilling AD diagnostic criteria. The Mini-Mental State Examination (MMSE) and the Severe Impairment Battery (SIB) are standard cognitive tests widely used to assess dementia in the general population. There are few studies using the MMSE and the SIB on subjects with DS where dementia is suspected. The aim of the present study was to analyse the appropriateness of the SIB and the MMSE in the cognitive assessment of aging subjects with DS. Methods: The SIB and the MMSE were administered to 45 subjects with DS (16 with Alzheimer’s disease and 29 without dementia), and the DMR questionnaire was given to their caregivers. Results: DS subjects with dementia had higher impairment levels than DS subjects without dementia in their social and total DMR scores, but no significant differences were found between the two groups in the SIB and MMSE scores or in cognitive DMR performance. Overall, SIB scores correlated significantly with MMSE results, total DMR, cognitive DMR, and social DMR. MMSE performance correlated significantly with total and cognitive DMR scores as well as SIB score. Conclusion: The SIB and the MMSE are useful assessment tools in monitoring cognitive function among subjects with DS and cognitive loss or dementia (AU)

Physical and functional cooperation between AP-1 and beta-catenin for the regulation of TCF-dependent genes.

Stabilization of cytoplasmic beta-catenin is a hallmark of a variety of cancers. The stabilized beta-catenin is able to translocate to the nucleus, where it acts as a transcriptional activator of T-cell factor (TCF)-regulated genes. beta-Catenin may cross-talk with many signalling cascades to activate target genes. Whether beta-catenin cooperates with AP-1, another transcriptional complex activated during tumorigenesis is not fully clarified. We show that beta-catenin co-immunoprecipitates with c-Jun and c-Fos. GST pull-down experiments indicate a physical association of the armadillo repeat domain of beta-catenin with the DNA-binding domain of c-Jun and of the C-terminal domain of beta-catenin with the N-terminal domain of c-Fos. Promoter studies indicate that overexpression of AP-1 activates the transcription of two beta-catenin target genes, cyclin D1 and c-myc, by a mechanism independent of the AP-1 site, and fully dependent on the TCF-binding site. We further demonstrate that AP-1/beta-catenin synergism is involved during serum-induced cyclin D1 transcriptional activation. We identify a TCF-binding site on the cyclin D1 promoter which binds in vivo a complex induced by serum, containing beta-catenin, TCF4, c-Fos, c-Jun, JunB and JunD. This novel mechanism of interaction between two signalling cascades might contribute to the potentiation of malignancy.

Estudio de evaluación del protocolo de vigilancia sanitaria específica del asma laboral mediante el instrumento Agree / No disponible

Se evalúa el Protocolo de Vigilancia Sanitaria Específica de Asma Laboral en seis dimensiones de calidad teórica mediante la aplicación del Instrumento AGREE. Para ello se establece un panel de cuatro evaluadores con experiencia en diferentes ámbitos de la Medicina del Trabajo. Resultados: El Instrumento AGREE se demostró válido para la evaluación de este protocolo existiendo un acuerdo entre evaluadores tanto en los puntos fuertes como débiles del protocolo. La Aplicabilidad de sus recomendaciones y la Participación de los implicados se mostraron como los puntos más débiles del protocolo y Muy mejorable en el Rigor científico. La independencia editorial y el Alcance y Objetivos se mostraron como los puntos más fuertes del protocolo. Conclusiones: Debería realizarse una revisión del protocolo en base a Guías o Pautas de elaboración recomendadas por instituciones de Calidad y dirigida prioritariamente a mejorar la evidencia y aplicabilidad de sus recomendaciones, así mismo el protocolo debe estar lo suficientemente documentado para permitir su reproducibilidad

There is evaluated the Protocol of Sanitary Specific Alertness of Labour Asthma in six dimensions of theoretical quality by means of the application of the Instrument AGREE. For it there is established a panel of four assessors by experience in different areas of the Medicine of the Work. Results: The Instrument AGREE was demonstrated valid for the evaluation of this protocol existing an agreement among assessors so much in the strong like weak points of the protocol. The Aplicabilidad of his recommendations and the Participation of the implied ones appeared as the weakest points of the protocol and very improvably in the scientific Rigor. The publishing independence and the Scope and Aims appeared as the strongest points of the protocol. Conclusions: a review of the protocol Should be realized on the basis of Guides or Guidelines of production recommended by qualit institutions and directed as a priority to improving the evidence and aplicabilidad of his recommendations, likewise the protocol must be the sufficiently documented to allow his reproducibility

Overexpression of regenerating islet-derived 1 alpha and 3 alpha genes in human primary liver tumors with beta-catenin mutations.

The Wnt/beta-catenin signaling pathway is activated in many human hepatocellular carcinomas (HCC). We tried to identify the genes involved in carcinogenesis and progression of HCC with beta-catenin mutations. We used PCR-based subtractive hybridization to compare gene expression between malignant and benign components of a human HCC occurring in pre-existing adenoma activated for beta-catenin. Two of the genes identified belong to the Regenerating gene (REG) family. They encode the Regenerating islet-derived 3 alpha (REG3A/HIP/PAP/REG-III) and 1 alpha (REG1A) proteins, both involved in liver and pancreatic regeneration and proliferation. Using siRNA directed against beta-catenin, we demonstrated that REG3A is a target of beta-catenin signaling in Huh7 hepatoma cells. The upregulation of REG3A and REG1A expression is significantly correlated to the beta-catenin status in 42 HCC and 28 hepatoblastomas characterized for their beta-catenin status. Thus, we report strong evidence that both genes are downstream targets of the Wnt pathway during liver tumorigenesis.

Hemangioma hepático gigante como causa de dispepsia. A propósito de un caso / Giant hepatic hemangioma as cause of dyspesia. Concerning a case

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Preliminary results of interferon-alpha therapy on woodchuck hepatitis virus-induced hepatocarcinogenesis: possible benefit in female transgenic mice.

BACKGROUND: C-myc activation is a potent oncogenic event in hepatocarcinogenesis. The aim of this study was to test the preventive effect of interferon-alpha (IFN-alpha) on the development of dysplasia and subsequent hepatocellular carcinoma (HCC) in transgenic (Tg) mice overexpressing c-myc in the liver. METHODS: The WHV/c-myc Tg mice recapitulating woodchuck hepatitis virus-induced hepatocarcinogenesis were treated with IFN-alpha, starting early in life until sacrifice at pre-neoplastic or neoplastic stages. Transgene expression was assessed by reverse transcription-polymerase chain reaction (RT-PCR), hepatocyte proliferation was assessed by bromodeoxyuridine incorporation and RT-PCR for proliferating cell nuclear antigen, and apoptosis was assessed by in situ nick-end-labeling of DNA. RESULTS: C-myc expression and hepatocyte proliferation were significantly reduced in treated female mice, without modification of apoptosis, correlating with a lower severity of dysplasia in 9/12 treated animals at pre-neoplastic stages. At the neoplastic stage, 2/3 treated females neither exhibited carcinoma nor dysplasia, while all 6/6 untreated mice and 3/3 treated males developed carcinomas. CONCLUSIONS: Inhibition of c-myc and hepatocyte proliferation by long-term administration of IFN-alpha was associated with a decrease, or a delay, of oncogenesis in the mouse Tg HCC model. Whether c-myc and hepatocyte proliferation down-regulation could be relevant parameters of IFN-alpha efficiency for hepatocarcinogenesis prevention in cirrhotic patients should be established.

[Endobronchial and laryngeal metastasis. An unusual form of dissemination of the hypernephroma]. / Metástasis endobronquiales y laríngeas. Una forma poco habitual de diseminación del hipernefroma.

OBJECTIVE: To describe uncommon forms of dissemination of hypernephroma. METHODS: A case of hypernephroma that metastasized to the laryngeal vallecula and bronchi is presented. Our findings were compared with those reported in the literature. The diagnostic, radiological, clinical aspects and route of dissemination of some atypical sites of metastasis are discussed. RESULTS/CONCLUSIONS: It is important to be familiar with these atypical sites of metastasis since these lesions may appear at the same time or before the primary tumor is detected. A high index of suspicion will make a major impact on treatment and prognosis. The radiological findings are undoubtedly of enormous value, although histological confirmation is necessary in order to make the correct diagnosis.

Genetics of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the human cancers clearly linked to viral infections. Although the major viral and environmental risk factors for HCC development have been unravelled, the oncogenic pathways leading to malignant transformation of liver cells have long remained obscure. Recent outcomes have been provided by extensive allelotype studies which resulted in a comprehensive overview of the main genetic abnormalities in HCC, including DNA copy gains and losses. The differential involvement of the p53 tumor-suppressor gene in tumors associated with various risk factors has been largely clarified. Evidence for a crucial role of the reactivation of the Wnt/beta-catenin pathway, through mutations in the beta-catenin and axin genes in 30-40% of liver tumors, represents a major breakthrough. It has also been shown that the Rb pathway is frequently disrupted by methylation-dependent silencing of the p16INK4A gene and stimulation of Rb degradation by a proteosomal subunit. Presently, the identification of candidate oncogenes and tumor suppressors in the most frequently altered chromosomal regions is a major challenge. Great insights will come from integrating the signals from different pathways operating at preneoplastic and neoplastic stages. This search might, in time, permit an accurate evaluation of the major targets for therapeutic treatments.

Hepatocellular carcinoma in WHV/N-myc2 transgenic mice: oncogenic mutations of beta-catenin and synergistic effect of p53 null alleles.

The intronless N-myc2 gene was originally identified as the major target of hepatitis virus insertion in woodchuck liver tumors. Here we report that transgenic mice carrying the N-myc2 gene controlled by woodchuck hepatitis virus (WHV) regulatory sequences are highly predisposed to liver cancer. In a WHV/N-myc2 transgenic line, hepatocellular carcinomas or adenomas arose in over 70% of mice, despite barely detectable expression of the methylated transgene in liver cells. Furthermore, a transgenic founder carrying unmethylated transgene sequences succumbed to a large liver tumor by the age of two months, demonstrating the high oncogenicity of the woodchuck N-myc2 retroposon. Stabilizing mutations or deletions of beta-catenin were found in 25% of liver tumors and correlated with reduced tumor latency (P<0.05), confirming the important role of beta-catenin activation in Myc-induced tumorigenesis. The ability of the tumor suppressor gene p53 to cooperate with N-myc2 in liver cell transformation was tested by introducing a p53-null allele into WHV/N-myc2 transgenic mice. The loss of one p53 allele in transgenic animals markedly accelerated the onset of liver cancer (P=0.0001), and most tumors of WHV/N-myc2 p53+/Delta mice harbored either a deletion of the wt p53 allele or a beta-catenin mutation. These findings provide direct evidence that activation of N-myc2 and reduction of p53 levels act synergistically during multistage carcinogenesis in vivo and suggest that different genetic pathways may underlie liver carcinogenesis initiated by a myc transgene. Oncogene (2000).

Activation of beta-catenin in epithelial and mesenchymal hepatoblastomas.

Wnt/beta-catenin signaling is frequently activated in cancer cells by stabilizing mutations of beta-catenin or loss-of-function mutations of the APC tumor suppressor gene. We have analysed the role of beta-catenin in the pathogenesis of hepatoblastoma (HB), an embryonic liver tumor occurring mainly in children under 2 years of age. Sequence analysis of the beta-catenin NH2-terminal domain in 18 epithelial and mixed HBs revealed missense mutations in the GSK3beta phosphorylation motif or interstitial deletions in 12 tumors (67%). In the remaining cases, no truncating mutation of APC could be evidenced. Immunohistochemical analysis of beta-catenin in 11 HBs demonstrated nuclear/cytoplasmic accumulation of the protein in all tumors analysed, with predominant nuclear beta-catenin immunostaining in undifferentiated cells. Membranous beta-catenin localization was preserved only in fetal-type tumoral hepatocytes and was associated with E-cadherin expression. Moreover, we show that beta-catenin is aberrantly overexpressed in a large spectrum of tumor components, including hepatocyte-like cells at various differentiation stages and heterologous elements such as squamous, osteoid and chrondroid tissues, and in occasional other mesenchymally-derived cells. These data strongly suggest that activation of beta-catenin signaling is an obligatory step in HB pathogenesis, and raise the possibility that it interferes with developmental signals that specify different tissue types at early stages of hepatic differentiation.

Nuclear accumulation of mutated beta-catenin in hepatocellular carcinoma is associated with increased cell proliferation.

Inappropriate activation of the Wnt pathway resulting from beta-catenin gene alterations has recently been implicated in the development of hepatocellular carcinoma (HCC). To explore the in vivo effects of mutated beta-catenin, HCC specimens from 32 patients carrying one or several tumors were screened for somatic mutations in exon 3 of the beta-catenin gene, and the expression and subcellular localization of beta-catenin was studied by immunohistochemistry. Missense mutations or interstitial deletions in beta-catenin exon 3 were detected in 12 of 35 (34%) HCC samples. After immunostaining, most tumors exhibited increased membranous and/or cytoplasmic expression of beta-catenin compared with adjacent nontumoral liver. Strong nuclear accumulation of beta-catenin was observed either focally or uniformly in 15 of 35 (43%) tumor specimens, but not in cirrhotic nodules or dysplastic liver cells in adjacent liver. Aberrant nuclear expression of beta-catenin was significantly associated with the presence of mutations in the beta-catenin gene (P < 0.005). Moreover, nuclear beta-catenin staining correlated significantly with increased Ki-67 proliferative index in tumor (P < 0.001) and seemed to be associated with poor outcome in patients with HCC. In conclusion, our data indicate that activation of the Wnt/beta-catenin pathway in HCC results mainly from somatic mutations in the beta-catenin gene and may promote tumor progression by stimulating tumor cell proliferation.