Supercell tornadoes are much stronger and wider than damage-based ratings indicate.

Tornadoes cause damage, injury, and death when intense winds impact structures. Quantifying the strength and extent of such winds is critical to characterizing tornado hazards. Ratings of intensity and size are based nearly entirely on postevent damage surveys [R. Edwards et al., Bull. Am. Meteorol. Soc. 94, 641-653 (2013)]. It has long been suspected that these suffer low bias [C. A. Doswell, D. W. Burgess, Mon. Weather Rev. 116, 495-501 (1988)]. Here, using mapping of low-level tornado winds in 120 tornadoes, we prove that supercell tornadoes are typically much stronger and wider than damage surveys indicate. Our results permit an accurate assessment of the distribution of tornado intensities and sizes and tornado wind hazards, based on actual wind-speed observations, and meaningful comparisons of the distribution of tornado intensities and sizes with theoretical predictions. We analyze data from Doppler On Wheels (DOW) radar measurements of 120 tornadoes at the time of peak measured intensity. In striking contrast to conventional damage-based climatologies, median tornado peak wind speeds are ∼60 m⋅s-1, capable of causing significant, Enhanced Fujita Scale (EF)-2 to -3, damage, and 20% are capable of the most intense EF-4/EF-5 damage. National Weather Service (NWS) EF/wind speed ratings are 1.2 to 1.5 categories (∼20 m⋅s-1) lower than DOW observations for tornadoes documented by both the NWS and DOWs. Median tornado diameter is 250 to 500 m, with 10 to 15% >1 km. Wind engineering tornado-hazard-model predictions and building wind resistance standards may require upward adjustment due to the increased wind-damage risk documented here.

The discovery of the benzazepine class of histamine H3 receptor antagonists.

This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties.

Structurally novel histamine H3 receptor antagonists GSK207040 and GSK334429 improve scopolamine-induced memory impairment and capsaicin-induced secondary allodynia in rats.

GSK207040 (5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-2-pyrazinecarboxamide) and GSK334429 (1-(1-methylethyl)-4-({1-[6-(trifluoromethyl)-3-pyridinyl]-4-piperidinyl}carbonyl)hexahydro-1H-1,4-diazepine) are novel and selective non-imidazole histamine H(3) receptor antagonists from distinct chemical series with high affinity for human (pK(i)=9.67+/-0.06 and 9.49+/-0.09, respectively) and rat (pK(i)=9.08+/-0.16 and 9.12+/-0.14, respectively) H(3) receptors expressed in cerebral cortex. At the human recombinant H(3) receptor, GSK207040 and GSK334429 were potent functional antagonists (pA(2)=9.26+/-0.04 and 8.84+/-0.04, respectively versus H(3) agonist-induced changes in cAMP) and exhibited inverse agonist properties (pIC(50)=9.20+/-0.36 and 8.59+/-0.04 versus basal GTPgammaS binding). Following oral administration, GSK207040 and GSK334429 potently inhibited cortical ex vivo [(3)H]-R-alpha-methylhistamine binding (ED(50)=0.03 and 0.35 mg/kg, respectively). Functional antagonism of central H(3) receptors was demonstrated by blockade of R-alpha-methylhistamine-induced dipsogenia in rats (ID(50)=0.02 and 0.11 mg/kg p.o. for GSK207040 and GSK334429, respectively). In more pathophysiologically relevant pharmacodynamic models, GSK207040 (0.1, 0.3, 1 and 3mg/kg p.o.) and GSK334429 (0.3, 1 and 3mg/kg p.o.) significantly reversed amnesia induced by the cholinergic antagonist scopolamine in a passive avoidance paradigm. In addition, GSK207040 (0.1, 0.3 and 1mg/kg p.o.) and GSK334429 (3 and 10mg/kg p.o.) significantly reversed capsaicin-induced reductions in paw withdrawal threshold, suggesting for the first time that blockade of H(3) receptors may be able to reduce tactile allodynia. Novel H(3) receptor antagonists such as GSK207040 and GSK334429 may therefore have therapeutic potential not only in dementia but also in neuropathic pain.

A cluster randomised controlled trial of educational prompts in diabetes care: study protocol.

BACKGROUND: Laboratory services have a central role in supporting screening, diagnosis, and management of patients. The increase in chronic disease management in primary care for conditions such as diabetes mellitus requires regular monitoring of patients' biochemical parameters. This process offers a route for improving the quality of care that patients receive by using test results as a vehicle for delivering educational messages as well as the test result itself. AIM: To develop and evaluate the effectiveness of a quality improvement initiative to improve the care of patients with diabetes using test report reminders. DESIGN: A programme of four cluster randomised controlled trials within one population of general practices. PARTICIPANTS: General practices in Newcastle-upon-Tyne, UK. INTERVENTION: Brief educational messages added to paper and electronic general practice laboratory test reports introduced over two phases. Phase One messages, attached to Haemoglobin A1c (HbA1c) reports, targeted glycaemic and cholesterol control. Phase Two messages, attached to albumin:creatinine ratio (ACR) reports, targeted blood pressure (BP) control and foot inspection. OUTCOMES: General practice mean levels of HbA1c and cholesterol (Phase One) and diastolic and systolic BP and proportions of patients having undergone foot inspections (Phase Two); number of tests requested.

GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer's disease brain and improves cognitive performance in preclinical models.

6-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) is a novel histamine H(3) receptor antagonist with high affinity for human (pK(i) = 9.59 -9.90) and rat (pK(i) = 8.51-9.17) H(3) receptors. GSK189254 is >10,000-fold selective for human H(3) receptors versus other targets tested, and it exhibited potent functional antagonism (pA(2) = 9.06 versus agonist-induced changes in cAMP) and inverse agonism [pIC(50) = 8.20 versus basal guanosine 5'-O-(3-[(35)S]thio)triphosphate binding] at the human recombinant H(3) receptor. In vitro autoradiography demonstrated specific [(3)H]GSK189254 binding in rat and human brain areas, including cortex and hippocampus. In addition, dense H(3) binding was detected in medial temporal cortex samples from severe cases of Alzheimer's disease, suggesting for the first time that H(3) receptors are preserved in late-stage disease. After oral administration, GSK189254 inhibited cortical ex vivo R-(-)-alpha-methyl[imidazole-2,5(n)-(3)H]histamine dihydrochloride ([(3)H]R-alpha-methylhistamine) binding (ED(50) = 0.17 mg/kg) and increased c-Fos immunoreactivity in prefrontal and somatosensory cortex (3 mg/kg). Microdialysis studies demonstrated that GSK189254 (0.3-3 mg/kg p.o.) increased the release of acetylcholine, noradrenaline, and dopamine in the anterior cingulate cortex and acetylcholine in the dorsal hippocampus. Functional antagonism of central H(3) receptors was demonstrated by blockade of R-alpha-methylhistamine-induced dipsogenia in rats (ID(50) = 0.03 mg/kg p.o.). GSK189254 significantly improved performance of rats in diverse cognition paradigms, including passive avoidance (1 and 3 mg/kg p.o.), water maze (1 and 3 mg/kg p.o.), object recognition (0.3 and 1 mg/kg p.o.), and attentional set shift (1 mg/kg p.o.). These data suggest that GSK189254 may have therapeutic potential for the symptomatic treatment of dementia in Alzheimer's disease and other cognitive disorders.