Results of an open label feasibility study of sodium valproate in people with McArdle disease

McArdle disease results from a lack of muscle glycogen phosphorylase in skeletal muscle tissue. Regenerating skeletal muscle fibres can express the brain glycogen phosphorylase isoenzyme. Stimulating expression of this enzyme could be a therapeutic strategy. Animal model studies indicate that sodium valproate (VPA) can increase expression of phosphorylase in skeletal muscle affected with McArdle disease. This study was designed to assess whether VPA can modify expression of brain phosphorylase isoenzyme in people with McArdle disease. This phase II, open label, feasibility pilot study to assess efficacy of six months treatment with VPA (20 mg/kg/day) included 16 people with McArdle disease. Primary outcome assessed changes in VO2peak during an incremental cycle test. Secondary outcomes included: phosphorylase enzyme expression in post-treatment muscle biopsy, total distance walked in 12 min, plasma lactate change (forearm exercise test) and quality of life (SF36). Safety parameters. 14 participants completed the trial, VPA treatment was well tolerated; weight gain was the most frequently reported drug-related adverse event. There was no clinically meaningful change in any of the primary or secondary outcome measures including: VO2peak, 12 min walk test and muscle biopsy to look for a change in the number of phosphorylase positive fibres between baseline and 6 months of treatment. Although this was a small open label feasibility study, it suggests that a larger randomised controlled study of VPA, may not be worthwhile

Rohlin Distance and the Evolution of Influenza A virus: Weak Attractors and Precursors

The evolution of the hemagglutinin amino acids sequences of Influenza A virus is studied by a method based on an informational metrics, originally introduced by Rohlin for partitions in abstract probability spaces. This metrics does not require any previous functional or syntactic knowledge about the sequences and it is sensitive to the correlated variations in the characters disposition. Its efficiency is improved by algorithmic tools, designed to enhance the detection of the novelty and to reduce the noise of useless mutations. We focus on the USA data from 1993/94 to 2010/2011 for A/H3N2 and on USA data from 2006/07 to 2010/2011 for A/H1N1 . We show that the clusterization of the distance matrix gives strong evidence to a structure of domains in the sequence space, acting as weak attractors for the evolution, in very good agreement with the epidemiological history of the virus. The structure proves very robust with respect to the variations of the clusterization parameters, and extremely coherent when restricting the observation window. The results suggest an efficient strategy in the vaccine forecast, based on the presence of "precursors" (or "buds") populating the most recent attractor.Comment: 13 pages, 5+4 figure

Incorporating radiomics into clinical trials: expert consensus on considerations for data-driven compared to biologically-driven quantitative biomarkers

Existing Quantitative Imaging Biomarkers (QIBs) are associated with known biological tissue characteristics and follow a well-understood path of technical, biological and clinical validation before incorporation into clinical trials. In radiomics, novel data-driven processes extract numerous visually imperceptible statistical features from the imaging data with no a priori assumptions on their correlation with biological processes. The selection of relevant features (radiomic signature) and incorporation into clinical trials therefore requires additional considerations to ensure meaningful imaging endpoints. Also, the number of radiomic features tested means that power calculations would result in sample sizes impossible to achieve within clinical trials. This article examines how the process of standardising and validating data-driven imaging biomarkers differs from those based on biological associations. Radiomic signatures are best developed initially on datasets that represent diversity of acquisition protocols as well as diversity of disease and of normal findings, rather than within clinical trials with standardised and optimised protocols as this would risk the selection of radiomic features being linked to the imaging process rather than the pathology. Normalisation through discretisation and feature harmonisation are essential pre-processing steps. Biological correlation may be performed after the technical and clinical validity of a radiomic signature is established, but is not mandatory. Feature selection may be part of discovery within a radiomics-specific trial or represent exploratory endpoints within an established trial; a previously validated radiomic signature may even be used as a primary/secondary endpoint, particularly if associations are demonstrated with specific biological processes and pathways being targeted within clinical trials

Sentinel lymph node metastasis from mammary ductal carcinoma in situ with microinvasion.

Axillary lymph node dissection (ALND) in patients with ductal carcinoma in situ with microinvasion (DCISM) of the breast was controversial, because of the relevant morbidity incurred by the procedure and the low incidence of axillary involvement. The introduction of the sentinel lymph node (SLN) biopsy as a minimally invasive procedure for axillary staging has prompted new interest in this issue. However, as DCISM is a rare type of cancer, data on the incidence of SLN metastasis are scarce. The aim of the present paper was therefore to assess the prevalence of SLN metastasis in a multi-institutional series of DCISM patients, in order to ascertain whether SLN biopsy might be justified as a standard procedure in the presence of microinvasive cancer. Between 1999 and 2004, 43 patients with a diagnosis of DCISM underwent SLN biopsy. Microinvasion was defined as one or more foci of invasion beyond the basal membrane, none exceeding 1mm. SLNs were examined following haematoxylin-eosin and immunohistochemical staining. SLN metastases were found in four out of 43 cases (9.3%). In one patient, SLN contained only micrometastasis. All four patients with positive SLN underwent complete ALND and in all these cases further metastatic axillary nodes were found. In conclusion, given the relevant incidence of nodal metastases and the low morbidity of the procedure, we believe that SLN biopsy should be considered in all patients with a diagnosis of DCISM. In cases of SLN involvement, even if micrometastatic, our policy is to perform a complete ALND

Sentinel lymph node metastasis from mammary ductal carcinoma in situ with microinvasion.

Abstract: Axillary lymph node dissection (ALND) in patients with ductal carcinoma in situ with microinvasion (DCISM) of the breast was controversial, because of the relevant morbidity incurred by the procedure and the low incidence of axillary involvement. The introduction of the sentinel lymph node (SLN) biopsy as a minimally invasive procedure for axillary staging has prompted new interest in this issue. However, as DCISM is a rare type of cancer, data on the incidence of SLN metastasis are scarce. The aim of the present paper was therefore to assess the prevalence of SLN metastasis in a multi-institutional series of DCISM patients, in order to ascertain whether SLN biopsy might be justified as a standard procedure in the presence of microinvasive cancer. Between 1999 and 2004, 43 patients with a diagnosis of DCISM underwent SLN biopsy. Microinvasion was defined as one or more foci of invasion beyond the basal membrane, none exceeding 1 mm. SLNs were examined following haematoxytin-eosin and immunohistochernical staining. SLN metastases were found in four out of 43 cases (9.3%). In one patient, SLN contained only micrometastasis. All four patients with positive SLN underwent complete ALND and in all these cases further metastatic axillary nodes were found. In conclusion, given the relevant incidence of nodal metastases and the low morbidity of the procedure, we believe that SLN biopsy should be considered in ail patients with a diagnosis of DCISM. In cases of SLN involvement, even if micrometastatic, our policy is to perform a complete ALND. (C) 2006 Elsevier Ltd. All rights reserved

Curso de Técnica de Pesquisa Bibliográfica: Programa-Padrão para a Universidade de São Paulo

Com base em pesquisa realizada nas bibliotecas de unidades de ensino superior (USP e outras), apresenta-se um programa-padrão mínimo para "Cursos de Técnicas da Pesquisa Bibliográfica" em âmbito da USP. Os pontos-chave do programa são esquematizados e comentados, com o intuito de servir de orientação ao desenvolvimento de um modelo adaptado às circunstâncias particulares. Sugere-se às bibliotecas das unidades em todas as áreas a confecção de um "Manual de Instruções" ou "Guia de Biblioteca" para seus usuários; ressalta-se a absoluta necessidade de apoio e compreensão da administração superior e corpo docente, para que os objetivos, propostos sejam atingidos na íntegra, com a introdução oficial nas unidades da USP do “Curso de Técnicas de Pesquisa Bibliográfica”

Role of axillary sentinel lymph node biopsy in patients with pure ductal carcinoma in situ of the breast.

BACKGROUND: Sentinel lymph node (SLN) biopsy is an effective tool for axillary staging in patients with invasive breast cancer. This procedure has been recently proposed as part of the treatment for patients with ductal carcinoma in situ (DCIS), because cases of undetected invasive foci and nodal metastases occasionally occur. However, the indications for SLN biopsy in DCIS patients are controversial.The aim of the present study was therefore to assess the incidence of SLN metastases in a series of patients with a diagnosis of pure DCIS. METHODS: A retrospective evaluation was made of a series of 102 patients who underwent SLN biopsy, and had a final histologic diagnosis of pure DCIS. Patients with microinvasion were excluded from the analysis. The patients were operated on in five Institutions between 1999 and 2004.Subdermal or subareolar injection of 30-50 MBq of 99 m-Tc colloidal albumin was used for SLN identification. All sentinel nodes were evaluated with serial sectioning, haematoxylin and eosin staining, and immunohistochemical analysis for cytocheratin. RESULTS: Only one patient (0.98%) was SLN positive. The primary tumour was a small micropapillary intermediate-grade DCIS and the SLN harboured a micrometastasis. At pathologic revision of the specimen, no detectable focus of microinvasion was found. CONCLUSION: Our findings indicate that SLN metastases in pure DCIS are a very rare occurrence. SLN biopsy should not therefore be routinely performed in patients who undergo resection for DCIS. SLN mapping can be performed, as a second operation, in cases in which an invasive component is identified in the specimen. Only DCIS patients who require a mastectomy should have SLN biopsy performed at the time of breast operation, since in these cases subsequent node mapping is not feasible

Estimate of Dementia Prevalence in a Community Sample from Sao Paulo, Brazil

Aims: To estimate dementia prevalence and describe the etiology of dementia in a community sample from the city of Sao Paulo, Brazil. Methods: A sample of subjects older than 60 years was screened for dementia in the first phase. During the second phase, the diagnostic workup included a structured interview, physical and neurological examination, laboratory exams, a brain scan, and DSM-IV criteria diagnosis. Results: Mean age was 71.5 years (n = 1,563) and 58.3% had up to 4 years of schooling (68.7% female). Dementia was diagnosed in 107 subjects with an observed prevalence of 6.8%. The estimate of dementia prevalence was 12.9%, considering design effect, nonresponse during the community phase, and positive and negative predictive values. Alzheimer`s disease was the most frequent cause of dementia (59.8%), followed by vascular dementia (15.9%). Older age and illiteracy were significantly associated with dementia. Conclusions: The estimate of dementia prevalence was higher than previously reported in Brazil, with Alzheimer`s disease and vascular dementia being the most frequent causes of dementia. Dementia prevalence in Brazil and in other Latin American countries should be addressed by additional studies to confirm these higher dementia rates which might have a sizable impact on countries` health services. Copyright (C) 2008 S. Karger AG, BaselFundacao de Apoio a Pesquisa do Estado de Sao Paulo (FAPESP)[01/05959-7

The neuropathological landscape of small vessel disease and Lewy pathology in a cohort of Hispanic and non-Hispanic White decedents with Alzheimer disease

Cerebrovascular and α-synuclein pathologies are frequently observed alongside Alzheimer disease (AD). The heterogeneity of AD necessitates comprehensive approaches to postmortem studies, including the representation of historically underrepresented ethnic groups. In this cohort study, we evaluated small vessel disease pathologies and α-synuclein deposits among Hispanic decedents (HD, n = 92) and non-Hispanic White decedents (NHWD, n = 184) from three Alzheimer's Disease Research Centers: Columbia University, University of California San Diego, and University of California Davis. The study included cases with a pathological diagnosis of Intermediate/High AD based on the National Institute on Aging- Alzheimer's Association (NIA-AA) and/or NIA-Reagan criteria. A 2:1 random comparison sample of NHWD was frequency-balanced and matched with HD by age and sex. An expert blinded to demographics and center origin evaluated arteriolosclerosis, cerebral amyloid angiopathy (CAA), and Lewy bodies/Lewy neurites (LBs/LNs) with a semi-quantitative approach using established criteria. There were many similarities and a few differences among groups. HD showed more severe Vonsattel grading of CAA in the cerebellum (p = 0.04), higher CAA density in the posterior hippocampus and cerebellum (ps = 0.01), and increased LBs/LNs density in the frontal (p = 0.01) and temporal cortices (p = 0.03), as determined by Wilcoxon's test. Ordinal logistic regression adjusting for age, sex, and center confirmed these findings except for LBs/LNs in the temporal cortex. Results indicate HD with AD exhibit greater CAA and α-synuclein burdens in select neuroanatomic regions when compared to age- and sex-matched NHWD with AD. These findings aid in the generalizability of concurrent arteriolosclerosis, CAA, and LBs/LNs topography and severity within the setting of pathologically confirmed AD, particularly in persons of Hispanic descent, showing many similarities and a few differences to those of NHW descent and providing insights into precision medicine approaches