Severity of disease and risk of malignant change in hereditary multiple exostoses. A genotype-phenotype study

We performed a prospective genotype-phenotype study using molecular screening and clinical assessment to compare the severity of disease and the risk of sarcoma in 172 individuals (78 families) with hereditary multiple exostoses. We calculated the severity of disease including stature, number of exostoses, number of surgical procedures that were necessary, deformity and functional parameters and used molecular techniques to identify the genetic mutations in affected individuals. Each arm of the genotype-phenotype study was blind to the outcome of the other. Mutations EXT1 and EXT2 were almost equally common, and were identified in 83% of individuals. Non-parametric statistical tests were used. There was a wide variation in the severity of disease. Children under ten years of age had fewer exostoses, consistent with the known age-related penetrance of this condition. The severity of the disease did not differ significantly with gender and was very variable within any given family. The sites of mutation affected the severity of disease with patients with EXT1 mutations having a significantly worse condition than those with EXT2 mutations in three of five parameters of severity (stature, deformity and functional parameters). A single sarcoma developed in an EXT2 mutation carrier, compared with seven in EXT1 mutation carriers. There was no evidence that sarcomas arose more commonly in families in whom the disease was more severe. The sarcoma risk in EXT1 carriers is similar to the risk of breast cancer in an older population subjected to breast-screening, suggesting that a role for regular screening in patients with hereditary multiple exostoses is justifiable. ©2004 British Editorial Society of Bone and Joint Surgery

Partial structure learning by subset Walsh transform.

Estimation of distribution algorithms (EDAs) use structure learning to build a statistical model of good solutions discovered so far, in an effort to discover better solutions. The non-zero coefficients of the Walsh transform produce a hypergraph representation of structure of a binary fitness function; however, computation of all Walsh coefficients requires exhaustive evaluation of the search space. In this paper, we propose a stochastic method of determining Walsh coefficients for hyperedges contained within the selected subset of the variables (complete local structure). This method also detects parts of hyperedges which cut the boundary of the selected variable set (partial structure), which may be used to incrementally build an approximation of the problem hypergraph

The principle of equivalence and projective structure in space-times

This paper discusses the extent to which one can determine the space-time metric from a knowledge of a certain subset of the (unparametrised) geodesics of its Levi-Civita connection, that is, from the experimental evidence of the equivalence principle. It is shown that, if the space-time concerned is known to be vacuum, then the Levi-Civita connection is uniquely determined and its associated metric is uniquely determined up to a choice of units of measurement, by the specification of these geodesics. It is further demonstrated that if two space-times share the same unparametrised geodesics and only one is assumed vacuum then their Levi-Civita connections are again equal (and so the other metric is also a vacuum metric) and the first result above is recovered.Comment: 23 pages, submitted to Classical and Quantum Gravit

Minimal walsh structure and ordinal linkage of monotonicity-invariant function classes on bit strings.

Problem structure, or linkage, refers to the interaction between variables in a black-box fitness function. Discovering structure is a feature of a range of algorithms, including estimation of distribution algorithms (EDAs) and perturbation methods (PMs). The complexity of structure has traditionally been used as a broad measure of problem difficulty, as the computational complexity relates directly to the complexity of structure. The EDA literature describes necessary and unnecessary interactions in terms of the relationship between problem structure and the structure of probabilistic graphical models discovered by the EDA. In this paper we introduce a classification of problems based on monotonicity invariance. We observe that the minimal problem structures for these classes often reveal that significant proportions of detected structures are unnecessary. We perform a complete classification of all functions on 3 bits. We consider nonmonotonicity linkage discovery using perturbation methods and derive a concept of directed ordinal linkage associated to optimization schedules. The resulting refined classification factored out by relabeling, shows a hierarchy of nine directed ordinal linkage classes for all 3-bit functions. We show that this classification allows precise analysis of computational complexity and parallelizability and conclude with a number of suggestions for future work

Medial temporal lobe function during emotional memory in early Alzheimer's disease, mild cognitive impairment and healthy ageing:an fMRI study

Background: Relative to intentional memory encoding, which quickly declines in Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD), incidental memory for emotional stimuli appears to deteriorate more slowly. We hypothesised that tests of incidental emotional memory may inform on different aspects of cognitive decline in MCI and AD.Methods: Patients with MCI, AD and Healthy Controls (HC) were asked to attend to emotional pictures (i.e., positive and neutral) sequentially presented during an fMRI session. Attention was monitored behaviourally. A surprise post-scan recognition test was then administered.Results: The groups remained attentive within the scanner. The post-scan recognition pattern was in the form of (HC = MCI) &gt; AD, with only the former group showing a clear benefit from emotional pictures. fMRI analysis of incidental encoding demonstrated clusters of activation in para-hippocampal regions and in the hippocampus in HC and MCI patients but not in AD patients. The pattern of activation observed in MCI patients tended to be greater than that found in HC.Conclusions: The results suggest that incidental emotional memory might offer a suitable platform to investigate, using behavioural and fMRI measures, subtle changes in the process of developing AD. These changes seem to differ from those found using standard episodic memory tests. The underpinnings of such differences and the potential clinical use of this methodology are discussed in depth.</p

iSRAP - A one-touch research tool for rapid profiling of small RNA-seq data

Small non-coding RNAs have been significantly recognized as the key modulators in many biological processes, and are emerging as promising biomarkers for several diseases. These RNA species are transcribed in cells and can be packaged in extracellular vesicles, which are small vesicles released from many biotypes, and are involved in intercellular communication. Currently, the advent of next-generation sequencing (NGS) technology for high-throughput profiling has further advanced the biological insights of non-coding RNA on a genome-wide scale and has become the preferred approach for the discovery and quantification of noncoding RNA species. Despite the routine practice of NGS, the processing of large data sets poses difficulty for analysis before conducting downstream experiments. Often, the current analysis tools are designed for specific RNA species, such as microRNA, and are limited in flexibility for modifying parameters for optimization. An analysis tool that allows for maximum control of different software is essential for drawing concrete conclusions for differentially expressed transcripts. Here, we developed a one-touch integrated small RNA analysis pipeline (iSRAP) research tool that is composed of widely used tools for rapid profiling of small RNAs. The performance test of iSRAP using publicly and in-house available data sets shows its ability of comprehensive profiling of small RNAs of various classes, and analysis of differentially expressed small RNAs. iSRAP offers comprehensive analysis of small RNA sequencing data that leverage informed decisions on the downstream analyses of small RNA studies, including extracellular vesicles such as exosomes

Dual task performance in early Alzheimer's disease, amnestic mild cognitive impairment and depression

Background. The dual task paradigm (Baddeley et al. 1986; Della Sala et al. 1995) has been proposed as a sensitive measure of Alzheimer's dementia, early in the disease process. Method. We investigated this claim by administering the modified dual task paradigm (utilising a pencil-and-paper version of a tracking task) to 33 patients with amnestic mild cognitive impairment (aMCI) and 10 with very early Alzheimer's disease, as well as 21 healthy elderly subjects and 17 controls with depressive symptoms. All groups were closely matched for age and pre-morbid intellectual ability. Results. There were no group differences in dual task performance, despite poor performance in episodic memory tests of the aMCI and early Alzheimer's disease groups. In contrast, the Alzheimer patients were specifically impaired in the trail-making test B, another commonly used test of divided attention. Conclusions. The dual task paradigm lacks sensitivity for use in the early differential diagnosis of Alzheimer's disease

Analytic philosophy for biomedical research: the imperative of applying yesterday's timeless messages to today's impasses

The mantra that "the best way to predict the future is to invent it" (attributed to the computer scientist Alan Kay) exemplifies some of the expectations from the technical and innovative sides of biomedical research at present. However, for technical advancements to make real impacts both on patient health and genuine scientific understanding, quite a number of lingering challenges facing the entire spectrum from protein biology all the way to randomized controlled trials should start to be overcome. The proposal in this chapter is that philosophy is essential in this process. By reviewing select examples from the history of science and philosophy, disciplines which were indistinguishable until the mid-nineteenth century, I argue that progress toward the many impasses in biomedicine can be achieved by emphasizing theoretical work (in the true sense of the word 'theory') as a vital foundation for experimental biology. Furthermore, a philosophical biology program that could provide a framework for theoretical investigations is outlined