The Neuromuscular Response to Spinal Manipulation: Quantifying the Effect of Pain with Electromyography

Objective To establish a methodology to quantify the neuromuscular response to spinal manipulation, develop a comprehensive date set including factors that affect the response, and compare the responses in both healthy participants and participants with acute and chronic low back pain. Methods Surface and indwelling electromyography at eight muscle locations were recorded during lumbar side-lying manipulations in 20 asymptomatic participants, 20 acute pain participants, and 20 chronic pain participants. Onset delay detection was optimized for signal detection failures and methodological comparisons were performed using a generalized linear model. The number of muscle responses and muscle activity onset delays in relation to the manipulation contact force were compared across participant subclasses using mixed linear regressions. Effect sizes for all comparisons were calculated using Cohen\u27s d. Results The method of muscle activity onset delay detection that best characterized the neuromuscular response to spinal manipulation was the double-threshold method with parameters of an 8 standard deviation amplitude threshold and a 10-msec duration threshold. In healthy participants, factors such as manipulation order and location had little effect on the neuromuscular response; however, the responding muscle location, layer and side revealed tendencies of lower response rates, and longer muscle activity onset delays as the distance from the manipulation location increased. Symptomatic participants had less muscle responses and longer muscle activity onset delays than the asymptomatic participants. Chronic pain participants had a greater tendency for shorter muscle activity onset delays than acute pain participants. Conclusions This study establishes a comprehensive database of both superficial lumbar and deep multifidus muscle activity and timing during spinal manipulation. The double-threshold method of muscle activity onset delay calculation is recommended over the cross-correlation method. Future studies in healthy participants focused on timing outcomes can be designed without regard for manipulation order and location within the parameters used in this study. Spinal manipulation may mediate pain through its influence on afferent activity of the muscle spindles and central nervous system. Participants in pain may experience more excitability in slower capsular reflex pathways than faster muscle spindle pathways compared to healthy participants, with the influence of the multifidi providing more pain-gating input to the central nervous system than superficial muscles. The neuromuscular response to spinal manipulation in participants in pain is dominated by the multifidus and is consistent with passive movements, as opposed to active movements that are dominated by superficial muscles

Liver Development, Regeneration, and Carcinogenesis

The identification of putative liver stem cells has brought closer the previously separate fields of liver development, regeneration, and carcinogenesis. Significant overlaps in the regulation of these processes are now being described. For example, studies in embryonic liver development have already provided the basis for directed differentiation of human embryonic stem cells and induced pluripotent stem cells into hepatocyte-like cells. As a result, the understanding of the cell biology of proliferation and differentiation in the liver has been improved. This knowledge can be used to improve the function of hepatocyte-like cells for drug testing, bioartificial livers, and transplantation. In parallel, the mechanisms regulating cancer cell biology are now clearer, providing fertile soil for novel therapeutic approaches. Recognition of the relationships between development, regeneration, and carcinogenesis, and the increasing evidence for the role of stem cells in all of these areas, has sparked fresh enthusiasm in understanding the underlying molecular mechanisms and has led to new targeted therapies for liver cirrhosis and primary liver cancers

Liquid biopsies for early diagnosis of brain tumours: in-silico mathematical biomarker modelling

Brain tumours are the biggest cancer killer in those under 40 and reduce life expectancy more than any other cancer. Blood-based liquid biopsies may aid early diagnosis, prediction and prognosis for brain tumours. It remains unclear whether known blood-based biomarkers, such as glial fibrillary acidic protein (GFAP), have the required sensitivity and selectivity. We have developed a novel in silico model which can be used to assess and compare blood-based liquid biopsies. We focused on GFAP, a putative biomarker for astrocytic tumours and glioblastoma multi-formes (GBMs). In silico modelling was paired with experimental measurement of cell GFAP concentrations and used to predict the tumour volumes and identify key parameters which limit detection. The average GBM volumes of 449 patients at Leeds Teaching Hospitals NHS Trust were also measured and used as a benchmark. Our model predicts that the currently proposed GFAP threshold of 0.12 ng ml(−1) may not be suitable for early detection of GBMs, but that lower thresholds may be used. We found that the levels of GFAP in the blood are related to tumour characteristics, such as vasculature damage and rate of necrosis, which are biological markers of tumour aggressiveness. We also demonstrate how these models could be used to provide clinical insight

New system for measuring cosmogenic Ne in terrestrial and extra-terrestrial rocks

Cosmogenic Ne isotopes are used for constraining the timing and rate of cosmological and Earth surface processes. We combined an automated gas extraction (laser) and purification system with a Thermo Fisher ARGUS VI mass spectrometer for high through-put, high precision Ne isotope analysis. For extra-terrestrial material with high cosmogenic Ne concentrations, we used multi-collection on Faraday detectors. Multiple measurements (n = 26) of 1.67 × 10−8 cm3 air-derived 20Ne yielded an uncertainty of 0.32%, and 21Ne/20Ne = 0.17% and 22Ne/20Ne = 0.09%. We reproduced the isotope composition of cosmogenic Ne in the Bruderheim chondrite and Imilac pallasite in a sub-ten mg sample. For lower Ne amounts that are typical of terrestrial samples, an electron multiplier detector was used in peak jumping mode. Repeated analysis of 3.2 × 10−11 cm3 STP 20Ne from air reproduced 21Ne/20Ne and 22Ne/20Ne with 1.1% and 0.58%, respectively, and 20Ne intensity with 1.7% (n = 103) over a 4-month period. Multiple (n = 8) analysis of cosmogenic Ne in CREU-1 quartz yielded 3.25 ± 0.24 × 108 atoms/g (2 s), which overlaps with the global mean value. The repeatability is comparable to the best data reported in the international experiments performed so far on samples that are 2–5× smaller. The ability to make precise Ne isotope determinations in terrestrial and extra-terrestrial samples that are significantly smaller than previously analysed suggests that the new system holds great promise for studies with limited material

Alcohol Induces Sensitization to Gluten in Genetically Susceptible Individuals: A Case Control Study

Background: The mechanisms of cerebellar degeneration attributed to prolonged and excessive alcohol intake remain unclear. Additional or even alternative causes of cerebellar degeneration are often overlooked in suspected cases of alcohol-related ataxia. The objectives of this study were two fold: (1) to investigate the prevalence of gluten-related serological markers in patients with alcohol-related ataxia and; (2) to compare the pattern of brain involvement on magnetic resonance imaging between patients with alcohol and gluten ataxias. Materials & Methods: Patients diagnosed with alcohol and gluten ataxias were identified from a retrospective review of patients attending a tertiary clinic. HLA genotype and serological markers of gluten-related disorders were recorded. Cerebellar volumetry, MR spectroscopy and voxel-based morphometric analyses were performed on patients and compared with matched control data. Results: Of 904 registered patients, 104 had alcohol ataxia and 159 had gluten ataxia. 61% of the alcohol ataxia group and 70% of the gluten ataxia group had HLA DQ2/DQ8 genotype compared to 30% in healthy local blood donors. 44% of patients with alcohol ataxia had antigliadin antibodies compared to 12% in the healthy local population and 10% in patients with genetically confirmed ataxias. None of the patients with alcohol ataxia and antigliadin antibodies had celiac disease compared to 40% in patients with gluten ataxia. The pattern of structural brain abnormality in patients with alcohol ataxia who had antigliadin antibodies differed from gluten ataxia and was identical to that of alcohol ataxia. Conclusions: Alcohol related cerebellar degeneration may, in genetically susceptible individuals, induce sensitization to gluten. Such sensitization may result from a primary cerebellar insult, but a more systemic effect is also possible. The duration and amount of exposure to alcohol may not be the only factors responsible for the cerebellar insult

Modelling Hepatic Endoderm Development: Highly Efficient Differentiation of Human Embryonic Stem Cells to Functional Hepatic Endoderm Requires ActivinA and Wnt3a Signalling.

Human embryonic stem cells (hESCs) are a valuable source of pluripotential primary cells. However, their homogeneous cellular differentiation to specific cell types _in vitro_ has proven difficult thus far. Wnt signalling has been shown to play important roles in coordinating development and we demonstrate that Wnt3a is differentially expressed at critical stages of human liver development _in vivo_. The essential role of Wnt3a in hepatocyte differentiation from hESCs is paralleled by our _in vitro_ model, demonstrating the importance of a physiological approach to cellular differentiation. Our studies provide compelling evidence that Wnt3a signaling is important for coordinated hepato-cellular function _in vitro_ and _in vivo_. In addition, we demonstrate Wnt3a facilitates clonal plating of hESCs capable of hepatic endoderm differentiation. These studies represent an important step forward toward the use of hESC-derived hepatocytes in biomedical applications and has opened the door to high through-put metabolic analysis of human liver function