Attainment rate as a surrogate indicator of the intervertebral neutral zone length in lateral bending: An in vitro proof of concept study

Background Lumbar segmental instability is often considered to be a cause of chronic low back pain. However, defining its measurement has been largely limited to laboratory studies. These have characterised segmental stability as the intrinsic resistance of spine specimens to initial bending moments by quantifying the dynamic neutral zone. However these measurements have been impossible to obtain in vivo without invasive procedures, preventing the assessment of intervertebral stability in patients. Quantitative fluoroscopy (QF), measures the initial velocity of the attainment of intervertebral rotational motion in patients, which may to some extent be representative of the dynamic neutral zone. This study sought to explore the possible relationship between the dynamic neutral zone and intervertebral rotational attainment rate as measured with (QF) in an in vitro preparation. The purpose was to find out if further work into this concept is worth pursuing. Method This study used passive recumbent QF in a multi-segmental porcine model. This assessed the intrinsic intervertebral responses to a minimal coronal plane bending moment as measured with a digital force guage. Bending moments about each intervertebral joint were calculated and correlated with the rate at which global motion was attained at each intervertebral segment in the first 10° of global motion where the intervertebral joint was rotating. Results Unlike previous studies of single segment specimens, a neutral zone was found to exist during lateral bending. The initial attainment rates for left and right lateral flexion were comparable to previously published in vivo values for healthy controls. Substantial and highly significant levels of correlation between initial attainment rate and neutral zone were found for left (Rho = 0.75, P = 0.0002) and combined left-right bending (Rho = 0.72, P = 0.0001) and moderate ones for right alone (Rho = 0.55, P = 0.0012). Conclusions This study found good correlation between the initial intervertebral attainment rate and the dynamic neutral zone, thereby opening the possibility to detect segmental instability from clinical studies. However the results must be treated with caution. Further studies with multiple specimens and adding sagittal plane motion are warranted

Protein Kinase C Iota Regulates Pancreatic Acinar-to-Ductal Metaplasia

Pancreatic acinar-to-ductal metaplasia (ADM) is associated with an increased risk of pancreatic cancer and is considered a precursor of pancreatic ductal adenocarcinoma. Transgenic expression of transforming growth factor alpha (TGF-α) or K-rasG12D in mouse pancreatic epithelium induces ADM in vivo. Protein kinase C iota (PKCι) is highly expressed in human pancreatic cancer and is required for the transformed growth and tumorigenesis of pancreatic cancer cells. In this study, PKCι expression was assessed in a mouse model of K-rasG12D-induced pancreatic ADM and pancreatic cancer. The ability of K-rasG12D to induce pancreatic ADM in explant culture, and the requirement for PKCι, was investigated. PKCι is elevated in human and mouse pancreatic ADM and intraepithelial neoplastic lesions in vivo. We demonstrate that K-rasG12D is sufficient to induce pancreatic ADM in explant culture, exhibiting many of the same morphologic and biochemical alterations observed in TGF-α-induced ADM, including a dependence on Notch activation. PKCι is highly expressed in both TGF-α- and K-rasG12D-induced pancreatic ADM and inhibition of PKCι significantly reduces TGF-α- and K-rasG12D-mediated ADM. Inhibition of PKCι suppresses K-rasG12D–induced MMP-7 expression and Notch activation, and exogenous MMP-7 restores K-rasG12D–mediated ADM in PKCι-depleted cells, implicating a K-rasG12D-PKCι-MMP-7 signaling axis that likely induces ADM through Notch activation. Our results indicate that PKCι is an early marker of pancreatic neoplasia and suggest that PKCι is a potential downstream target of K-rasG12D in pancreatic ductal metaplasia in vivo

Local governance in the new Police Scotland:Renegotiating power, recognition and responsiveness

A marked, but by no means universal, trend in Europe over the last decade or so has been the centralization or amalgamation of regional police organizations into larger or single units. Scotland is a case in point, its eight regional services becoming one Police Scotland in April 2013. Although the reform process was relatively consensual, the new organization has been the subject of numerous controversies, some of which reflect an actual or perceived loss of the local in Scottish policing. Drawing on a qualitative study of the emerging local governance arrangements, we explore the negotiated character of large-scale organizational reform, demonstrating that it is best understood as a process not an event. We also argue that appeals to localism are not mere expressions of sentiment and resistance to change. They reflect the particular historical development of policing and public service delivery in Scotland at the level of municipal government, but also strong convictions that policing should be subject to democratic deliberation and should recognize and be responsive to those subject to it – what we argue here are necessary functions of police governance in general

Genetic modifiers in rare disorders: the case of fragile X syndrome.

Methods employed in genome-wide association studies are not feasible ways to explore genotype-phenotype associations in rare disorders due to limited statistical power. An alternative approach is to examine relationships among specific single nucleotide polymorphisms (SNPs), selected a priori, and behavioural characteristics. Here, we adopt this strategy to examine relationships between three SNPs (5-HTTLPR, MAOA, COMT) and specific clinically-relevant behaviours that are phenotypic of fragile X syndrome (FXS) but vary in severity and frequency across individuals. Sixty-four males with FXS participated in the current study. Data from standardised informant measures of challenging behaviour (defined as physical aggression, property destruction, stereotyped behaviour, and self-injury), autism symptomatology, attention-deficit-hyperactivity-disorder characteristics, repetitive behaviour and mood/interest and pleasure were compared between each SNP genotype. No association was observed between behavioural characteristics and either 5-HTTLPR (serotonin) or MAOA (monoamine oxidase) genotypes. However, compared to the COMT (dopamine) AG and GG genotypes, the AA genotype was associated with greater interest and pleasure in the environment, and with reduced risk for property destruction, stereotyped behaviour and compulsive behaviour. The results suggest that common genetic variation in the COMT genotype affecting dopamine levels in the brain may contribute to the variability of challenging and repetitive behaviours and interest and pleasure in this population. This study identifies a role for additional genetic risk in understanding the neural and genetic mechanisms contributing to phenotypic variability in neurodevelopmental disorders, and highlights the merit of investigating SNPs that are selected a priori on a theoretical basis in rare populations

Simulating Microdosimetry in a Virtual Hepatic Lobule

The liver plays a key role in removing harmful chemicals from the body and is therefore often the first tissue to suffer potentially adverse consequences. To protect public health it is necessary to quantitatively estimate the risk of long-term low dose exposure to environmental pollutants. Animal testing is the primary tool for extrapolating human risk but it is fraught with uncertainty, necessitating novel alternative approaches. Our goal is to integrate in vitro liver experiments with agent-based cellular models to simulate a spatially extended hepatic lobule. Here we describe a graphical model of the sinusoidal network that efficiently simulates portal to centrilobular mass transfer in the hepatic lobule. We analyzed the effects of vascular topology and metabolism on the cell-level distribution following oral exposure to chemicals. The spatial distribution of metabolically inactive chemicals was similar across different vascular networks and a baseline well-mixed compartment. When chemicals were rapidly metabolized, concentration heterogeneity of the parent compound increased across the vascular network. As a result, our spatially extended lobule generated greater variability in dose-dependent cellular responses, in this case apoptosis, than were observed in the classical well-mixed liver or in a parallel tubes model. The mass-balanced graphical approach to modeling the hepatic lobule is computationally efficient for simulating long-term exposure, modular for incorporating complex cellular interactions, and flexible for dealing with evolving tissues

Role of Matrix Metalloproteinase 13 in Both Endochondral and Intramembranous Ossification during Skeletal Regeneration

Extracellular matrix (ECM) remodeling is important during bone development and repair. Because matrix metalloproteinase 13 (MMP13, collagenase-3) plays a role in long bone development, we have examined its role during adult skeletal repair. In this study we find that MMP13 is expressed by hypertrophic chondrocytes and osteoblasts in the fracture callus. We demonstrate that MMP13 is required for proper resorption of hypertrophic cartilage and for normal bone remodeling during non-stabilized fracture healing, which occurs via endochondral ossification. However, no difference in callus strength was detected in the absence of MMP13. Transplant of wild-type bone marrow, which reconstitutes cells only of the hematopoietic lineage, did not rescue the endochondral repair defect, indicating that impaired healing in Mmp13−/− mice is intrinsic to cartilage and bone. Mmp13−/− mice also exhibited altered bone remodeling during healing of stabilized fractures and cortical defects via intramembranous ossification. This indicates that the bone phenotype occurs independently from the cartilage phenotype. Taken together, our findings demonstrate that MMP13 is involved in normal remodeling of bone and cartilage during adult skeletal repair, and that MMP13 may act directly in the initial stages of ECM degradation in these tissues prior to invasion of blood vessels and osteoclasts

Australian chiropractic sports medicine: half way there or living on a prayer?

Sports chiropractic within Australia has a chequered historical background of unorthodox individualistic displays of egocentric treatment approaches that emphasise specific technique preference and individual prowess rather than standardised evidence based management. This situation has changed in recent years with the acceptance of many within sports chiropractic to operate under an evidence informed banner and to embrace a research culture. Despite recent developments within the sports chiropractic movement, the profession is still plagued by a minority of practitioners continuing to espouse certain marginal and outlandish technique systems that beleaguer the mainstream core of sports chiropractic as a cohesive and homogeneous group. Modern chiropractic management is frequently multimodal in nature and incorporates components of passive and active care. Such management typically incorporates spinal and peripheral manipulation, mobilisation, soft tissue techniques, rehabilitation and therapeutic exercises. Externally, sports chiropractic has faced hurdles too, with a lack of recognition and acceptance by organized and orthodox sports medical groups. Whilst some arguments against the inclusion of chiropractic may be legitimate due to its historical baggage, much of the argument appears to be anti-competitive, insecure and driven by a closed-shop mentality.sequently, chiropractic as a profession still remains a pariah to the organised sports medicine world. Add to this an uncertain continuing education system, a lack of protection for the title 'sports chiropractor', a lack of a recognized specialist status and a lack of support from traditional chiropractic, the challenges for the growth and acceptance of the sports chiropractor are considerable. This article outlines the historical and current challenges, both internal and external, faced by sports chiropractic within Australia and proposes positive changes that will assist in recognition and inclusion of sports chiropractic in both chiropractic and multi-disciplinary sports medicine alike