Hepatic Efficiency Tests with a Report on the Galactose Tolerance Test

The last quarter of a century has witnessed many advances in medicine, and not the least of these has been the application of biochemical and biophysical methods in the investigation of disease. The success which has attended these efforts, is probably best seen in the discovery of Insulin, but other advances perhaps not so epoch-making, have been made, and it is impossible at present to foretell to what heights they will lead us, or whether they will ultimately assist at all in the elucidation of the numerous problems awaiting solution. These methods have resulted in the evolution of so-called "function tests" applied to various organs of the body, and in spite of numerous theoretical objections which can be lodged against them, and they are many, there can be ho doubt that they have yielded results which have proved useful both in diagnosis and prognosis though the ultimate interpretation of these results may be a matter of dispute. In the following paper the writer is concerned with the. liver, the various tests which have been evolved for estimating whether disease be present, and if so, to what extent, and their value in the prognosis of disease. Various difficulties, which, though mainly theoretical, affect the practical value of conclusions, are met with at the outset. 1. An organ has usually many functions, while the tests applied, usually measure but one of these. 2. Deficiency in the particular function investigated does not necessarily imply deficiency in all, or even in any other function. 3. The large reserve power possessed by most organs of the body. This is well seen in the case of the liver. Up to three fourths of liver substance may be removed, without affecting appreciably the bodily economy. 4. The powers of hypertrophy and hyperplasia possessed by the liver and the ability thus to compensate for the effects of disease. 5. The particular function tested may be possessed by other organs to a varying extent, and so deficiency in an organ may be compensated by over-activity in another. 6. Each chemical process is but a part in the total metabolismof the body, and failure in one link of the chain of reactions will react on all, so that it is necessary to rule out coincident disease in other organs. Finally the question arises - what is the position when a laboratory finding is at variance with a clinical one? This can only arise from a mistaken conception as to the relative value of clinical and laboratory data. There is no essential difference between estimating the capacity of the heart for doing work and assessing the power of the kidney to excrete urea. Each item is but one link in the diagnostic chain, and must be considered in relation to the whole The task of interpretation of results is therefore very great, and caution necessary before definite conclusions can be drawn

GPNN: Power Studies and Applications of a Neural Network Method for Detecting Gene-Gene Interactions in Studies of Human Disease

The identification and characterization of genes that influence the risk of common, complex multifactorial disease primarily through interactions with other genes and environmental factors remains a statistical and computational challenge in genetic epidemiology. We have previously introduced a genetic programming optimized neural network (GPNN) as a method for optimizing the architecture of a neural network to improve the identification of gene combinations associated with disease risk. The goal of this study was to evaluate the power of GPNN for identifying high-order gene-gene interactions. We were also interested in applying GPNN to a real data analysis in Parkinson\u27s disease

Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis

Angiogenesis-mediated progression of micrometastasis to lethal macrometastasis is the major cause of death in cancer patients. Here, using mouse models of pulmonary metastasis, we identify bone marrow (BM)-derived endothelial progenitor cells (EPCs) as critical regulators of this angiogenic switch. We show that tumors induce expression of the transcription factor Id1 in the EPCs and that suppression of Id1 after metastatic colonization blocked EPC mobilization, caused angiogenesis inhibition, impaired pulmonary macrometastases, and increased survival of tumor-bearing animals. These findings establish the role of EPCs in metastatic progression in preclinical models and suggest that selective targeting of EPCs may merit investigation as a therapy for cancer patients with lung metastases

Evaluation of the Sysmex XN-550, a Novel Compact Haematology analyser from the XN-L (R) series, compared to the XN-20 system

INTRODUCTION: The XN-550 is a new, automated, compact, haematology analyser designed to generate a full blood count with a standard five-part white blood cell differential and an immature granulocyte count, as well as an optional reticulocyte and optical platelet (PLT) counts. The aim of the study was to evaluate the performance of the XN-550 and compare it to the established XN-20 system. METHODS: We evaluated the basic parameter and special measurement channels of the XN-550, using the XN-20 (which has a similar operating system), as a reference analyser. Precision, carry-over and throughput evaluations were performed. In addition, a total of 202 samples including normal controls and various pathological samples were studied for comparability. RESULTS: Good correlations with the reference analyser were obtained for all parameters except basophils. The XN-550 offers impedance and optical PLT counts and the latter showed a better correlation and less scatter than the impedance count and was comparable to the XN-20 fluorescent count at PLT counts ≤40×109/L. Precision was good, and no significant carry-over was detected. CONCLUSIONS: The XN-550 was simple and easy to use, while maintaining the good diagnostic sensitivity seen with high-range systems such as the XN-20, making this compact device suitable for near-patient services and smaller satellite laboratories

Plasma biomarkers inclusive of α-synuclein/amyloid-beta40 ratio strongly correlate with Mini-Mental State Examination score in Parkinson's disease and predict cognitive impairment

Plasma biomarkers for Parkinson’s disease (PD) diagnosis that carry predictive value for cognitive impairment are valuable. We explored the relationship of Mini-Mental State Examination (MMSE) score with plasma biomarkers in PD patients and compared results to vascular dementia (VaD) and normal controls. The predictive accuracy of an individual biomarker on cognitive impairment was evaluated using area under the receiver operating characteristic curve (AUROC), and multivariate logistic regression was applied to evaluate predictive accuracy of biomarkers on cognitive impairment; 178 subjects (41 PD, 31 VaD and 106 normal controls) were included. In multiple linear regression analysis of PD patients, α-synuclein, anti-α-synuclein, α-synuclein/Aβ40 and anti-α-synuclein/Aβ40 were highly predictive of MMSE score in both full model and parsimonious model (R2 = 0.838 and 0.835, respectively) compared to non-significant results in VaD group (R2 = 0.149) and in normal controls (R2 = 0.056). Α-synuclein and anti-α-synuclein/Aβ40 were positively associated with MMSE score, and anti-α-synuclein, α-synuclein/Aβ40 were negatively associated with the MMSE score among PD patients (all Ps < 0.005). In the AUROC analysis, anti-α-synuclein (AUROC = 0.788) and anti-α-synuclein/Aβ40 (AUROC = 0.749) were significant individual predictors of cognitive impairment. In multivariate logistic regression, full model of combined biomarkers showed high accuracy in predicting cognitive impairment (AUROC = 0.890; 95%CI 0.796–0.984) for PD versus controls, as was parsimonious model (AUROC = 0.866; 95%CI 0.764–0.968). In conclusion, simple combination of biomarkers inclusive of α-synuclein/Aβ40 strongly correlates with MMSE score in PD patients versus controls and is highly predictive of cognitive impairment

Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization

Tumors build vessels by cooption of pre-existing vasculature and de novo recruitment of bone marrow (BM)-derived endothelial progenitor cells (EPCs). However, the contribution and the functional role of EPCs in tumor neoangiogenesis are controversial. Therefore, by using genetically marked BM progenitor cells, we demonstrate the precise spatial and temporal contribution of EPCs to the neovascularization of three transplanted and one spontaneous breast tumor in vivo using high-resolution microscopy and flow cytometry. We show that early tumors recruit BM-derived EPCs that differentiate into mature BM-derived endothelial cells (ECs) and luminally incorporate into a subset of sprouting tumor neovessels. Notably, in later tumors, these BM-derived vessels are diluted with non-BM-derived vessels from the periphery, which accounts for purported differences in previously published reports. Furthermore, we show that specific ablation of BM-derived EPCs with alpha-particle-emitting anti-VE-cadherin antibody markedly impaired tumor growth associated with reduced vascularization. Our results demonstrate that BM-derived EPCs are critical components of the earliest phases of tumor neoangiogenesis

Right Research: Modelling Sustainable Research Practices in the Anthropocene

The year 2020 started with a massive bushfire crisis in south eastern Australia, resulting in disruption to many communities, the loss of lives and businesses, an estimated loss of a billion animals and the dirtiest air on the planet in the cities of Sydney, Newcastle and Canberra. With record-high temperatures and a punishing draught lasting several years, the Australian bush was primed to explode into flames. With lightning strikes in national parks, the spontaneous eruptions of bushfire spread from the north coast to the south and inland towards the alpine regions of New South Wales and Victoria. With the very hot year of 2019 affecting other parts of the planet in 2020, the Antarctic Peninsula reached a record 65 degrees Fahrenheit. The chapter that follows reflects the new progressive politics of climate change that emerged in 2019 with large mass demonstrations taking place in Australia and around the world and examines the critical role of universities in the mitigation of climate catastrophe. The following interventions are variably focused on the concept of ‘Living Labs’ where thinking is developed within a problem-solving ethos. The three contributions here offer ways to think about sustainability with specific reference to waste recovery, environmental awareness in urban settings and the contribution that a ‘repair’ mentality can make to a shared and re-cycled economy. With a clear-eyed recommendation that mitigation of climate change starts locally, the premise of the paper is that people can work with what is available as local solutions to specific problems. The impact of this approach can be essential to people who sense the impending catastrophe and who may have experienced the crisis directly through compromises in their health outcomes, the experience of trauma and the loss of property and livelihoods, though through no fault of their own. The links through the Western Sydney University campus, common ground to the authors to both its small bushland outpost and further to the local community it serves, suggest that the boundaries of the campus are permeable – and that Living Labs are both a means and metaphor for thinking about how the campus opens learning and knowledge creation about sustainability for its students, staff and community constituents

Disease-specific, neurosphere-derived cells as models for brain disorders

There is a pressing need for patient-derived cell models of brain diseases that are relevant and robust enough to produce the large quantities of cells required for molecular and functional analyses. We describe here a new cell model based on patient-derived cells from the human olfactory mucosa, the organ of smell, which regenerates throughout life from neural stem cells. Olfactory mucosa biopsies were obtained from healthy controls and patients with either schizophrenia, a neurodevelopmental psychiatric disorder, or Parkinson's disease, a neurodegenerative disease. Biopsies were dissociated and grown as neurospheres in defined medium. Neurosphere-derived cell lines were grown in serum-containing medium as adherent monolayers and stored frozen. By comparing 42 patient and control cell lines we demonstrated significant disease-specific alterations in gene expression, protein expression and cell function, including dysregulated neurodevelopmental pathways in schizophrenia and dysregulated mitochondrial function, oxidative stress and xenobiotic metabolism in Parkinson's disease. The study has identified new candidate genes and cell pathways for future investigation. Fibroblasts from schizophrenia patients did not show these differences. Olfactory neurosphere-derived cells have many advantages over embryonic stem cells and induced pluripotent stem cells as models for brain diseases. They do not require genetic reprogramming and they can be obtained from adults with complex genetic diseases. They will be useful for understanding disease aetiology, for diagnostics and for drug discovery

Intraspecific divergence associated with a biogeographic barrier and climatic models show future threats and long-term decline of a rainforest conifer

A capacity to foresee the shift in species’ range and the demographic response to future climate change is integral to effective conservation planning. Here we model the future climate-driven range shift, and compare it with past range shift, along a latitudinal gradient in two population groups of a late-successional rainforest conifer (Podocarpus elatus), genetically differentiated over the Clarence River Corridor biogeographic barrier (Northern NSW, East Australian Rainforests). Climate envelope modelling of the past-current-future distributions of the two groups and a coalescent-based isolation-with-migration model investigated divergence times and effective population sizes among the current genetic disjunctions in the species. This suggests differential range shift (i.e. expansion in the north and contraction in the south) will continue in the future, with a southern range shift also occurring in both climatic models. The origin of the Clarence River Corridor dividing the two population groups was inferred by molecular analysis to be prior to the last glacial maximum (LGM). Another divergence in the south (19 ka) is indicative of slow consistent habitat contractions since the LGM (21 ka). We recommend the southern and Macleay Overlap Zone (far-eastern Australia) populations as priority areas for protection based upon intraspecific diversity and past-current-future habitat suitability. The integrated approach shows that this widely distributed species is more at risk than expected from current climate change and other anthropogenic effects.Rohan Mellick, Maurizio Rossetto, Chris Allen, Peter D. Wilson, Robert S. Hill and Andrew Low