Aryl Ethers from Arenediazonium Tetrafluoroborate Salts: from Neat Reactions to Solvent-mediated Effects

A general procedure for the synthesis of various aryl ethers via the thermal decomposition of benzenediazonium tetrafluoroborate salts is described. Studies performed in neat alcohol at 60°C gave aryl ethers in yields ranging from 0-73%. Upon completion of a series of reactions, the effect of solvent was explored to expand the scope and relevance of this procedure. It was found that even solvents that are traditionally non-nucleophilic gave rise to products including bi-aryls and N-aryl acetamides. The utilization of an ionic liquid, l-butyl-4-methylpyridinium tetrafluoroborate, resulted in yields comparable to reactions performed in neat alcoholic solvents

Practice patterns for acute ischemic stroke workup: A longitudinal population‐based study

Background We examined practice patterns of inpatient testing to identify stroke etiologies and treatable risk factors for acute ischemic stroke recurrence. Methods and Results We identified stroke cases and related diagnostic testing from four 1‐year study periods (July 1993 to June 1994, 1999, 2005, and 2010) of the Greater Cincinnati/Northern Kentucky Stroke Study. Patients aged ≥18 years were included. We focused on evaluation of extracranial arteries for carotid stenosis and assessment of atrial fibrillation because randomized controlled trials supported treatment of these conditions for stroke prevention across all 4 study periods. In each study period, we also recorded stroke etiology, as determined by diagnostic testing and physician adjudication. An increasing proportion of stroke patients received assessment of both extracranial arteries and the heart over time (50%, 58%, 74%, and 78% in the 1993–1994, 1999, 2005, and 2010 periods, respectively; P &lt;0.0001 for trend), with the most dramatic individual increases in echocardiography (57%, 63%, 77%, and 83%, respectively). Concurrently, we observed a decrease in strokes of unknown etiology (47%, 48%, 41%, and 38%, respectively; P &lt;0.0001 for trend). We also found a significant increase in strokes of other known causes (32%, 25%, 45% and 59%, respectively; P &lt;0.0001 for trend). Conclusions Stroke workup for treatable causes of stroke are being used more frequently over time, and this is associated with a decrease in cryptogenic strokes. Future study of whether better determination of treatable stroke etiologies translates to a decrease in stroke recurrence at the population level will be essential. </jats:sec

Interrogating a Hexokinase-Selected Small-Molecule Library for Inhibitors of Plasmodium falciparum Hexokinase

This is the published version.Parasites in the genus Plasmodium cause disease throughout the tropic and subtropical regions of the world. P. falciparum, one of the deadliest species of the parasite, relies on glycolysis for the generation of ATP while it inhabits the mammalian red blood cell. The first step in glycolysis is catalyzed by hexokinase (HK). While the 55.3-kDa P. falciparum HK (PfHK) shares several biochemical characteristics with mammalian HKs, including being inhibited by its products, it has limited amino acid identity (∼26%) to the human HKs, suggesting that enzyme-specific therapeutics could be generated. To that end, interrogation of a selected small-molecule library of HK inhibitors has identified a class of PfHK inhibitors, isobenzothiazolinones, some of which have 50% inhibitory concentrations (IC50s) of <1 μM. Inhibition was reversible by dilution but not by treatment with a reducing agent, suggesting that the basis for enzyme inactivation was not covalent association with the inhibitor. Lastly, six of these compounds and the related molecule ebselen inhibited P. falciparum growth in vitro (50% effective concentration [EC50] of ≥0.6 and <6.8 μM). These findings suggest that the chemotypes identified here could represent leads for future development of therapeutics against P. falciparum

Stable incidence but declining case-fatality rates of subarachnoid hemorrhage in a population

Objective: To characterize temporal trends in subarachnoid hemorrhage (SAH) incidence and outcomes over 5 time periods in a large population-based stroke study in the United States. Methods: All SAHs among residents of the Greater Cincinnati/Northern Kentucky region at least 20 years of age were identified and verified via study physician review in 5 distinct year-long study periods between 1988 and 2010. We abstracted demographics, care patterns, and outcomes, and we compared incidence and case-fatality rates across the study periods. Results: The incidence of SAH in the 5 study periods (age-, race-, and sex-adjusted to the 2000 US population) was 8.8 (95% confidence interval 6.8–10.7), 9.2 (7.2–11.2), 10.0 (8.0–12.0), 9.0 (7.1–10.9), and 7.7 (6.0–9.4) per 100,000, respectively; the trend in incidence rates from 1988 to 2010 was not statistically significant (p = 0.22). Advanced neurovascular imaging, endovascular coiling, and neurologic intensive care unit availability increased significantly over time. All-cause 5-day (32%–18%, p = 0.01; for trend), 30-day (46%–25%, p = 0.001), and 90-day (49%–29%, p = 0.001) case-fatality rates declined from 1988 to 2010. When we included only proven or highly likely aneurysmal SAH, the declines in case-fatality were no longer statistically significant. Conclusions: Although the incidence of SAH remained stable in this population-based region, 5-day, 30-day, and 90-day case-fatality rates declined significantly. Advances in surgical and medical management, along with systems-based changes such as the emergence of neurocritical care units, are potential explanations for the reduced case-fatality

Sex-specific stroke incidence over time in the Greater Cincinnati/Northern Kentucky Stroke Study

OBJECTIVE: Recent data suggest stroke incidence is decreasing over time, but it is unknown whether incidence is decreasing in women and men to the same extent. METHODS: Within our population of 1.3 million, all incident strokes among residents ≥20 years old were ascertained at all hospitals during July 1993-June 1994 and calendar years 1999, 2005, and 2010. A sampling scheme was used to ascertain out-of-hospital cases. Sex-specific incidence rates per 100,000 among black and white participants, age- and race-adjusted, were standardized to the 2000 US Census population. Trends over time by sex were compared; a Bonferroni correction was applied for multiple comparisons. RESULTS: Over the 4 study periods, there were 7,710 incident strokes; 57.2% (n = 4,412) were women. Women were older than men (mean ± SE 72.4 ± 0.34 vs 68.2 ± 0.32, p < 0.001). Incidence of all strokes decreased over time in men (263 [confidence interval 246-281] to 192 [179-205], p < 0.001) but not in women (217 [205-230] to 198 [187-210], p = 0.15). Similar sex differences were seen for ischemic stroke (men, 238 [223-257] to 165 [153-177], p < 0.01; women, 193 [181-205] to 173 [162-184], p = 0.09). Incidence of all strokes and of ischemic strokes was similar between women and men in 2010. Incidence of intracerebral hemorrhage and subarachnoid hemorrhage were stable over time in both sexes. CONCLUSIONS: Decreases in stroke incidence over time are driven by a decrease in ischemic stroke in men. Contrary to previous study periods, stroke incidence rates were similar by sex in 2010. Future research is needed to understand why the decrease in ischemic stroke incidence is more pronounced in men

High-Resolution Ice Cores from US ITASE (West Antarctica): Development and Validation of Chronologies and Determination of Precision and Accuracy

Shallow ice cores were obtained from widely distributed sites across the West Antarctic ice sheet, as part of the United States portion of the International Trans-Antarctic Scientific Expedition (US ITASE) program. The US ITASE cores have been dated by annual-layer counting, primarily through the identification of summer peaks in non-sea-salt sulfate (nssSO(4)(2-)) concentration. Absolute dating accuracy of better than 2 years and relative dating accuracy better than 1 year is demonstrated by the identification of multiple volcanic marker horizons in each of the cores, Tambora, Indonesia (1815), being the most prominent. Independent validation is provided by the tracing of isochronal layers from site to site using high-frequency ice-penetrating radar observations, and by the timing of mid-winter warming events in stable-isotope ratios, which demonstrate significantly better than 1 year accuracy in the last 20 years. Dating precision to 1 month is demonstrated by the occurrence of summer nitrate peaks and stable-isotope ratios in phase with nssSO(4)(2-), and winter-time sea-salt peaks out of phase, with phase variation of \u3c 1 month. Dating precision and accuracy are uniform with depth, for at least the last 100 years

Potentially Missed Diagnosis of Ischemic Stroke in the Emergency Department in the Greater Cincinnati/Northern Kentucky Stroke Study

Missed diagnoses of acute ischemic stroke (AIS) in the ED may result in lost opportunities to treat AIS. Our objectives were to describe the rate and clinical characteristics of missed AIS in the ED, to determine clinical predictors of missed AIS, and to report tissue plasminogen (tPA) eligibility among those with missed strokes

Genome screen in familial intracranial aneurysm

Research articl

Behavioural responses to unexpected changes in reward quality

Successive negative contrast (SNC) effects are changes in anticipatory or consummatory behaviour when animals unexpectedly receive a lower value reward than they have received previously. SNC effects are often assumed to reflect frustration and appear to be influenced by background affective state. However, alternative explanations of SNC, such as the functional-search hypothesis, do not necessarily imply an aversive affective state. We tested 18 dogs in a SNC paradigm using a patch foraging task. Dogs were tested in two conditions, once with the low value reward in all of five trials (unshifted) and once when reward value was altered between high and low (shifted). Following a reward downshift, subjects showed a SNC effect by switching significantly more often between patches compared to the unshifted condition. However, approach latency, foraging time and quantity consumed did not differ between conditions, suggesting non-affective functional search behaviour rather than frustration. There was no relationship between strength of SNC and anxiety-related behaviours as measured in a novel object test and a personality questionnaire (C-BARQ). However, associations with the C-BARQ scores for Trainability and Stranger directed aggression suggest a possible link with behavioural flexibility and coping style. While reward quality clearly affects incentive motivation, the relationship between SNC, frustration and background affective state requires further exploration