The industrial revolution transformed the productive power of societies. It did so by vastly increasing the individual productivity, thus delivering whole populations from poverty. In this new ...account by one of the world's acknowledged authorities the central issue is not simply how the revolution began but still more why it did not quickly end. The answer lay in the use of a new source of energy. Pre-industrial societies had access only to very limited energy supplies. As long as mechanical energy came principally from human or animal muscle and heat energy from wood, the maximum attainable level of productivity was bound to be low. Exploitation of a new source of energy in the form of coal provided an escape route from the constraints of an organic economy but also brought novel dangers. Since this happened first in England, its experience has a special fascination, though other countries rapidly followed suit.
By the early nineteenth century England was very different economically from its continental neighbours. It was wealthier, growing more rapidly, more heavily urbanised, and far less dependent upon ...agriculture. A generation ago it was normal to attribute these differences to the 'industrial revolution' and to suppose that this was mainly the product of recent change, but no longer. Current estimates suggest only slow growth during the period from 1760–1840. This implies that the economy was much larger and more advanced by 1760 than had previously been supposed and suggests that growth in the preceding century or two must have been decisive in bringing about the 'divergence' of England. Sir E. A. Wrigley, the leading historian of industrial Britain, here examines the issues which arise in this connection from three viewpoints: economic growth; the transformation of the urban-rural balance; and demographic change in the seventeenth and eighteenth centuries.
Energy and the English Industrial Revolution Wrigley, E. A
Philosophical transactions - Royal Society. Mathematical, Physical and engineering sciences/Philosophical transactions - Royal Society. Mathematical, physical and engineering sciences,
03/2013, Letnik:
371, Številka:
1986
Journal Article
Recenzirano
Odprti dostop
Societies before the Industrial Revolution were dependent on the annual cycle of plant photosynthesis for both heat and mechanical energy. The quantity of energy available each year was therefore ...limited, and economic growth was necessarily constrained. In the Industrial Revolution, energy usage increased massively and output rose accordingly. The energy source continued to be plant photosynthesis, but accumulated over a geological age in the form of coal. This poses a problem for the future. Fossil fuels are a depleting stock, whereas in pre-industrial time the energy source, though limited, was renewed each year.
Neuropathic pain following spinal cord injury is associated with altered thalamic biochemistry, structure and function, which may disturb central processing and play a key role in the persistent ...experience of pain.
There is increasing evidence relating thalamic changes to the generation and/or maintenance of neuropathic pain. We have recently reported that neuropathic orofacial pain is associated with altered thalamic anatomy, biochemistry, and activity, which may result in disturbed thalamocortical oscillatory circuits. Despite this evidence, it is possible that these thalamic changes are not responsible for the presence of pain per se, but result as a consequence of the injury. To clarify this subject, we compared brain activity and biochemistry in 12 people with below-level neuropathic pain after complete thoracic spinal cord injury with 11 people with similar injuries and no neuropathic pain and 21 age- and gender-matched healthy control subjects. Quantitative arterial spinal labelling was used to measure thalamic activity, and magnetic resonance spectroscopy was used to determine changes in neuronal variability quantifying N-acetylaspartate and alterations in inhibitory function quantifying gamma amino butyric acid. This study revealed that the presence of neuropathic pain is associated with significant changes in thalamic biochemistry and neuronal activity. More specifically, the presence of neuropathic pain after spinal cord injury is associated with significant reductions in thalamic N-acetylaspartate, gamma amino butyric acid content, and blood flow in the region of the thalamic reticular nucleus. Spinal cord injury on its own did not account for these changes. These findings support the hypothesis that neuropathic pain is associated with altered thalamic structure and function, which may disturb central processing and play a key role in the experience of neuropathic pain.
Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a ...number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.
Osimertinib is a potent and selective EGFR tyrosine kinase inhibitor (EGFR-TKI) of both sensitizing and T790M resistance mutations. To treat metastatic brain disease, blood-brain barrier (BBB) ...permeability is considered desirable for increasing clinical efficacy.
We examined the level of brain penetration for 16 irreversible and reversible EGFR-TKIs using multiple
and
BBB preclinical models.
osimertinib was the weakest substrate for human BBB efflux transporters (efflux ratio 3.2).
rat free brain to free plasma ratios (Kpuu) show osimertinib has the most BBB penetrance (0.21), compared with the other TKIs (Kpuu ≤ 0.12). PET imaging in Cynomolgus macaques demonstrated osimertinib was the only TKI among those tested to achieve significant brain penetrance (
%ID 1.5, brain/blood Kp 2.6). Desorption electrospray ionization mass spectroscopy images of brains from mouse PC9 macrometastases models showed osimertinib readily distributes across both healthy brain and tumor tissue. Comparison of osimertinib with the poorly BBB penetrant afatinib in a mouse PC9 model of subclinical brain metastases showed only osimertinib has a significant effect on rate of brain tumor growth.
These preclinical studies indicate that osimertinib can achieve significant exposure in the brain compared with the other EGFR-TKIs tested and supports the ongoing clinical evaluation of osimertinib for the treatment of EGFR-mutant brain metastasis. This work also demonstrates the link between low
transporter efflux ratios and increased brain penetrance
supporting the use of
transporter assays as an early screen in drug discovery.
Paul Bairoch began an essay analyzing nineteenth-century urban growth in continental Europe. He noted that he had hoped to begin his survey earlier in time but scarcity of relevant data had prevented ...him from doing so. He was therefore obliged to concentrate on urban growth in the nineteenth century. Here, Wrigley considers the three variables he listed in relation to urban growth in England and examines the scale of the contrast between England and the Continent in this regard.
Several measures can quantify thoracic kyphosis from radiographs, yet their suitability for people with osteoporosis remains uncertain. The aim of this study was to examine the validity and ...reliability of the vertebral centroid and Cobb angles in people with osteoporosis.
Lateral radiographs of the thoracic spine were captured in 31 elderly women with osteoporosis. Thoracic kyphosis was measured globally (T1-T12) and regionally (T4-T9) using Cobb and vertebral centroid angles. Multisegmental curvature was also measured by fitting polynomial functions to the thoracic curvature profile. Canonical and Pearson correlations were used to examine correspondence; agreement between measures was examined with linear regression.
Moderate to high intra- and inter-rater reliability was achieved (SEM = 0.9-4.0 degrees ). Concurrent validity of the simple measures was established against multisegmental curvature (r = 0.88-0.98). Strong association was observed between the Cobb and centroid angles globally (r = 0.84) and regionally (r = 0.83). Correspondence between measures was moderate for the Cobb method r = 0.72), yet stronger for the centroid method (r = 0.80). The Cobb angle was 20% greater for regional measures due to the influence of endplate tilt.
Regional Cobb and centroid angles are valid and reliable measures of thoracic kyphosis in people with osteoporosis. However, the Cobb angle is biased by endplate tilt, suggesting that the centroid angle is more appropriate for this population.
All organic economies were subject to constraints upon growth for reasons familiar to the classical economists, but their relative success in coping with these constraints differed substantially. ...This is visible both when comparing different areas at the same point in time and when comparing the circumstances of a given economy at different points in time. In this article the state of the English economy in 1300 is compared with its state in 1800. At the former date the balance between output and population was unfavourable. A run of poor harvests spelled grave and widespread suffering. Five hundred years later this had ceased to be true. The particular focus of the article is upon the significance of a rising level of productivity per head in agriculture, not simply in supplying food but in providing the raw materials and energy needed if industry and transport were to expand. In the circumstances of an organic economy both were heavily dependent upon the 'surplus' made available by a productive agriculture after meeting the needs of the population for food.
The epidermal growth factor receptor (EGFR) harboring activating mutations is a clinically validated target in non-small-cell lung cancer, and a number of inhibitors of the EGFR tyrosine kinase ...domain, including osimertinib, have been approved for clinical use. Resistance to these therapies has emerged due to a variety of molecular events including the C797S mutation which renders third-generation C797-targeting covalent EGFR inhibitors considerably less potent against the target due to the loss of the key covalent-bond-forming residue. We describe the medicinal chemistry optimization of a biochemically potent but modestly cell-active, reversible EGFR inhibitor starting point with sub-optimal physicochemical properties. These studies culminated in the identification of compound 12 that showed improved cell potency, oral exposure, and in vivo activity in clinically relevant EGFR-mutant-driven disease models, including an Exon19 deletion/T790M/C797S triple-mutant mouse xenograft model.
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