Tissue engineered humanized bone supports human hematopoiesis in vivo

Advances in tissue-engineering have resulted in a versatile tool-box to specifically design a tailored microenvironment for hematopoietic stem cells (HSCs) in order to study diseases that develop within this setting. However, most current in vivo models fail to recapitulate the biological processes seen in humans. Here we describe a highly reproducible method to engineer humanized bone constructs that are able to recapitulate the morphological features and biological functions of the HSC niches. Ectopic implantation of biodegradable composite scaffolds cultured for 4 weeks with human mesenchymal progenitor cells and loaded with rhBMP-7 resulted in the development of a chimeric bone organ including a large number of human mesenchymal cells which were shown to be metabolically active and capable of establishing a humanized microenvironment supportive of the homing and maintenance of human HSCs. A syngeneic mouse-to-mouse transplantation assay was used to prove the functionality of the tissue-engineered ossicles. We predict that the ability to tissue engineer a morphologically intact and functional large-volume bone organ with a humanized bone marrow compartment will help to further elucidate physiological or pathological interactions between human HSCs and their native niches.

Genetics and genomics of ankylosing spondylitis

Ankylosing spondylitis (AS) is a common, highly heritable arthropathy, the pathogenesis of which is poorly understood. The mechanism by which the main gene for the disease, HLA-B27, leads to AS is unknown. Genetic and genomic studies have demonstrated involvement of the interleukin-23 (IL-23) signaling pathway in AS, a finding which has stimulated much new research into the disease and has led to therapeutic trials. Several other genes and genetic regions, including further major histocompatibility complex (MHC) and non-MHC loci, have been shown to be involved in the disease, but it is not clear yet how they actually induce the condition. These findings have shown that there is a strong genetic overlap between AS and Crohn's disease in particular, although there are also major differences in the genes involved in the two conditions, presumably explaining their different presentations. Genomic and proteomic studies are in an early phase but have potential both as diagnostic/prognostic tools and as a further hypothesis-free tool to investigate AS pathogenesis. Given the slow progress in studying the mechanism of association of HLA-B27 with AS, these may prove to be more fruitful approaches to investigating the pathogenesis of the disease. © 2009 John Wiley & Sons A/S.

Path algebra for mobile robots

In this paper, we introduce a path algebra well suited for navigation in environments that can be abstracted as topological graphs. From this path algebra, we derive algorithms to reduce routes in such environments. The routes are reduced in the sense that they are shorter (contain fewer edges), but still connect the endpoints of the initial routes. Contrary to planning methods descended from Disjktra’s Shortest Path Algorithm like D , the navigation methods derived from our path algebra do not require any graph representation. We prove that the reduced routes are optimal when the graphs are without cycles. In the case of graphs with cycles, we prove that whatever the length of the initial route, the length of the reduced route is bounded by a constant that only depends on the structure of the environment.

Genetic studies of disorders of calcium crystal deposition

In summary, although many factors are likely to be involved in regulating calcification and ossification processes, studies of the causation of articular chondrocalcinosis and disorders of spinal ossification, such as DISH and OPLL, implicate control over inorganic pyrophosphate levels as being one of the most important factors in their aetiopathogenesis. The findings of these studies may prove relevant to other rheumatic diseases in which ectopic ossification occurs, such as AS.

Medical negligence, causation and 'exceptional cases' under the civil liability legislation

Under the civil liability legislation enacted in most Australian jurisdictions, factual causation will be established if, on the balance of probabilities, the claimant can prove that the defendant's negligence was 'a necessary condition of the occurrence of the [claimant's] harm'. Causation will then be satisfied by showing that the harm would not have occurred 'but for' the defendant's breach of their duty of care. However, in an exceptional or appropriate case, sub-section 2 of the legislation provides that if the 'but for' test is not met, factual causation may instead be determined in accordance with other 'established principles'. In such a case, 'the court is to consider (amongst other relevant things) whether or not and why responsibility for the harm should be imposed' on the negligent party.

Australian court holds Google is responsible for linking to defamatory website

The South Australian Supreme Court this week found that Google is legally responsible when its search results link to defamatory content on the web. In this long-running case, Dr Janice Duffy has been trying for more than six years to clear her name and remove links to defamatory material when people search for her using Google. The main culprit is the US based website Ripoff Reports, where people have posted negative reviews of Dr Duffy. Under United States law, defamation is very hard to prove, and US websites are not liable for comments made by their users. Since it was not possible to get harmful or abusive comments removed from the source, Dr Duffy instead asked Google to remove the links from its search results. Google removed some of these links, but only from its Australian domain (google.com.au), and it left many of them active. This latest court decision is a big win for Dr Duffy. The court found that once Google was alerted to the defamatory material, it was then under an obligation to act to censor its search results and prevent further harm to Dr Duffy’s reputation.

In vivo velocity vector imaging and time-resolved strain rate measurements in the wall of blood vessels using MRI

In this paper, we present a new approach for velocity vector imaging and time-resolved measurements of strain rates in the wall of human arteries using MRI and we prove its feasibility on two examples: in vitro on a phantom and in vivo on the carotid artery of a human subject. Results point out the promising potential of this approach for investigating the mechanics of arterial tissues in vivo.

Rank regression for analysis of clustered data: A natural induced smoothing approach

We consider rank regression for clustered data analysis and investigate the induced smoothing method for obtaining the asymptotic covariance matrices of the parameter estimators. We prove that the induced estimating functions are asymptotically unbiased and the resulting estimators are strongly consistent and asymptotically normal. The induced smoothing approach provides an effective way for obtaining asymptotic covariance matrices for between- and within-cluster estimators and for a combined estimator to take account of within-cluster correlations. We also carry out extensive simulation studies to assess the performance of different estimators. The proposed methodology is substantially Much faster in computation and more stable in numerical results than the existing methods. We apply the proposed methodology to a dataset from a randomized clinical trial.

A revisit to Pope's cohort analysis

Gulland's [Gulland, J.A., 1965. Estimation of mortality rates. Annex to Arctic Fisheries Working Group Report (meeting in Hamburg, January 1965). ICES. C.M. 1965, Doc. No. 3 (mimeographed)] virtual population analysis (VPA) is commonly used for studying the dynamics of harvested fish populations. However, it necessitates the solving of a nonlinear equation for the instantaneous rate of fishing mortality of the fish in a population. Pope [Pope, J.G., 1972. An investigation of the accuracy of Virtual Population Analysis using cohort analysis. ICNAF Res. Bull. 9, 65-74. Also available in D.H. Cushing (ed.) (1983), Key Papers on Fish Populations, p. 291-301, IRL Press, Oxford, 405 p.] eliminated this necessity in his cohort analysis by approximating its underlying age- and time-dependent population model. His approximation has since become one of the most commonly used age- and time-dependent fish population models in fisheries science. However, some of its properties are not well understood. For example, many assert that it describes the dynamics of a fish population, from which the catch of fish is taken instantaneously in the middle of the year. Such an assertion has never been proven, nor has its implied instantaneous rate of fishing mortality of the fish of a particular age at a particular time been examined, nor has its implied catch equation been derived from a general catch equation. In this paper, we prove this assertion, examine its implied instantaneous rate of fishing mortality of the fish of a particular age at a particular time, derive its implied catch equation from a general catch equation, and comment on how to structure an age- and time-dependent population model to ensure its internal consistency. This work shows that Gulland's (1965) virtual population analysis and Pope's (1972) cohort analysis lie at the opposite end of a continuous spectrum as a general model for a seasonally occurring fishery; Pope's (1972) approximation implies an infinitely large instantaneous rate of fishing mortality of the fish of a particular age at a particular time in a fishing season of zero length; and its implied catch equation has an undefined instantaneous rate of fishing mortality of the fish in a population, but a well-defined cumulative instantaneous rate of fishing mortality of the fish in the population. This work also highlights a need for a more careful treatment of the times of start and end of a fishing season in fish population models.

GABAB Receptor antagonist CGP46381 inhibits form-deprivation myopia development in guinea pigs

The aim was to investigate the effects of the GABAB receptor antagonist, CGP46381, on form-deprivation myopia (FDM) in guinea pigs. Twenty-four guinea pigs had monocular visual deprivation induced using a diffuser for 11 days (day 14 to 25). The deprived eyes were treated with daily subconjunctival injections (100 μl) of either 2% CGP46381, 0.2% CGP46381, or saline or received no injection. The fellow eyes were left untreated. Another six animals received no treatment. At the start and end of the treatment period, ocular refractions were measured using retinoscopy and vitreous chamber depth (VCD) and axial length (AL) using A-scan ultrasound. All of the deprived eyes developed relative myopia (treated versus untreated eyes, P < 0.05). The amount of myopia was significantly affected by the drug treatment (one-way ANOVA, P < 0.0001). The highest dose tested, 2% CGP46381, significantly inhibited myopia development compared to saline (2% CGP46381: -1.08 ± 0.40 D, saline: -4.33 ± 0.67 D, P < 0.01). The majority of these effects were due to less AL (2% CGP46381: 0.03 ± 0.01 mm, saline: 0.13 ± 0.02 mm, P < 0.01) and VCD (2% CGP46381: 0.02 ± 0.01 mm, saline: 0.08 ± 0.01 mm, P < 0.01) elongation. The lower dose tested, 0.2% CGP46381, did not significantly inhibit FDM (P > 0.05). Subconjunctival injections of CGP46381 inhibit FDM development in guinea pigs in a dose-dependent manner.

Can exploring natural recovery from substance misuse in psychosis assist with treatment? A review of current research

Substance misuse in people with psychosis presents significant problems, but trials of treatments to address it show little sustained advantage over control conditions. An examination of mechanisms underpinning unassisted improvements may assist in the refinement of co-morbidity treatments. This study reviewed existing research on natural recovery from substance misuse in people with psychosis. To address this issue, a systematic search identified only 7 articles that fulfilled the criteria. Their results suggest that people with psychosis report similar reasons to change as do non-psychotic groups, although they did not clarify whether the relative frequencies or priority orders were the same. Differences involved issues relating to the disorder and the functional problems faced by this group: receipt of treatment for mental health difficulties, worsening of mental health difficulties, and homelessness. The current research on reasons for change in people with psychosis is sparse and has significant limitations, and as yet it offers little inspiration for new treatments. A more fertile source may prove to be a detailed investigation of successful substance control strategies that are used in self-management by this group.