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1.  Alterations of N-3 Polyunsaturated Fatty Acid-Activated K2P Channels in Hypoxia-Induced Pulmonary Hypertension 
Basic & clinical pharmacology & toxicology  2013;113(4):10.1111/bcpt.12092.
Polyunsaturated fatty acid (PUFA)-activated two-pore domain potassium channels (K2P) have been proposed to be expressed in the pulmonary vasculature. However, their physiological or pathophysiological roles are poorly defined. Here we tested the hypothesis that PUFA-activated K2P are involved in pulmonary vasorelaxation and that alterations of channel expression are pathophysiologically linked to pulmonary hypertension.
Expression of PUFA-activated K2P in the murine lung was investigated by quantitative reverse-transcription polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), by patch clamp (PC), and myography. K2P-gene expression was examined in chronic hypoxic mice.
QRT-PCR showed that the K2P2.1 and K2P6.1 were the predominantly expressed K2P in the murine lung. IHC revealed protein expression of K2P2.1 and K2P6.1 in the endothelium of pulmonary arteries and of K2P6.1 in bronchial epithelium. PC showed pimozide-sensitive K2P-like K+-current activated by docosahexaenoic acid (DHA) in freshly isolated endothelial cells as well as DHA-induced membrane hyperpolarization. Myography on pulmonary arteries showed that DHA-induced concentration-dependent and instantaneous relaxations that were resistant to endothelial removal and inhibition of NO and prostacyclin synthesis and to a cocktail of blockers of calcium-activated K+ channels but were abolished by high extracellular (30 mM) K+-concentration. Gene expression and protein of K2P2.1 were not altered in chronic hypoxic mice while K2P6.1 was up-regulated by fourfold.
In conclusion, the PUFA-activated K2P2.1 and K2P6.1 are expressed in murine lung and functional K2P-like channels contribute to endothelium-hyperpolarization and pulmonary artery relaxation. The increased K2P6.1-gene expression may represent a novel counter-regulatory mechanism in pulmonary hypertension, and suggest that arterial K2P2.1 and K2P6.1 could be novel therapeutic targets.
PMCID: PMC3835666  PMID: 23724868
endothelium; K2P2.1; K2P6.1; lung; polyunsaturated fatty acid; pulmonary hypertension; vasorelaxation
Hypertension  2011;58(4):672-678.
K2P6.1, a member of the Two-Pore Domain K channel family, is highly expressed in the vascular system; however its function is unknown. We tested the following hypotheses. K2P6.1 regulates (1) systemic blood pressure, (2) the contractile state of arteries, (3) vascular smooth muscle cell migration, (4) proliferation, and/or (5) volume regulation. Mice lacking K2P6.1 (KO) were generated by deleting exon 1 of Kcnk6. Mean arterial blood pressure in both anesthetized and awake KO mice was increased by 17 ± 2 and 26 ± 3 mmHg respectively (p<0.05). The resting membrane potential in freshly dispersed vascular smooth muscle cells was depolarized by 17 ± 2 mV in the KO compared to WT littermates (p<0.05). The contractile responses to KCl (p<0.05) and BAY K 8644 (p<0.01), an activator of L-type calcium channels, were enhanced in isolated segments of aorta from KO mice. However there was no difference in current density of L-type calcium channels. Responses to U46619, an agent which activates rho kinase, showed an enhanced contraction in aorta from KO mice (p<0.001). The BAY K 8644-mediated increase in contraction was decreased to WT levels when treated with Y27632, a rho kinase inhibitor, (p<0.05). K2P6.1 does not appear to be involved with migration, proliferation, or volume regulation in cultured vascular smooth muscle cells. We conclude that K2P6.1 deficiency induces vascular dysfunction and hypertension through a mechanism that may involve smooth muscle cell depolarization and enhanced rho kinase activity.
PMCID: PMC3205080  PMID: 21876070
Two-pore domain potassium channels (K2P); Hypertension; Resting membrane potential; TWIK-2; Kcnk6; K2P6.1; Rho kinase
3.  Effect of Isoflurane on Aortic Impedance in Mice 
Conference Proceedings  2009;2009:1104-1105.
Isoflurane is the most commonly used anesthetic in mice. We studied the effect of low and high levels of isoflurane (also a potent coronary vasodilator) on aortic impedance in mice. Aortic impedance was determined using pressure and flow velocity signals at baseline (B, pentobarbital anesthesia), low (Iso1, 1%), and high (Iso2.5, 2.5%) levels of isoflurane. Significant differences were observed in peak and mean flow velocities, systolic, diastolic, mean and pulse pressures at B and Iso2.5. However in impedance indices only peripheral vascular resistance was significantly different. No changes were observed in the harmonic components that represent pulsatile characteristics of the aorta. Peak left ventricular (LV) pressure was significantly lower at Iso2.5 when compared to B, but ±dP/dt and τ (time constant of LV relaxation) did not change significantly indicating that LV contractility was unaffected. These results show that various levels of isoflurane cause significant changes in vascular hemodynamics and care must be taken to minimize these differences when using isoflurane as an anesthesia.
PMCID: PMC3341611  PMID: 19964748
Aortic impedance; Aortic pressure; Aortic flow velocity; Anesthesia; LV contractility
4.  The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial 
The purpose of this study was to compare urate-lowering (UL) efficacy and safety of daily febuxostat and allopurinol in subjects with gout and serum urate (sUA) ≥ 8.0 mg/dL in a six-month trial.
Subjects (n = 2,269) were randomized to febuxostat 40 mg or 80 mg, or allopurinol 300 mg (200 mg in moderate renal impairment). Endpoints included the proportion of all subjects with sUA <6.0 mg/dL and the proportion of subjects with mild/moderate renal impairment and sUA <6.0 mg/dL. Safety assessments included blinded adjudication of each cardiovascular (CV) adverse event (AE) and death.
Comorbidities included: renal impairment (65%); obesity (64%); hyperlipidemia (42%); and hypertension (53%). In febuxostat 40 mg, febuxostat 80 mg, and allopurinol groups, primary endpoint was achieved in 45%, 67%, and 42%, respectively. Febuxostat 40 mg UL was statistically non-inferior to allopurinol, but febuxostat 80 mg was superior to both (P < 0.001). Achievement of target sUA in subjects with renal impairment was also superior with febuxostat 80 mg (72%; P < 0.001) compared with febuxostat 40 mg (50%) or allopurinol (42%), but febuxostat 40 mg showed greater efficacy than allopurinol (P = 0.021). Rates of AEs did not differ across treatment groups. Adjudicated (APTC) CV event rates were 0.0% for febuxostat 40 mg and 0.4% for both febuxostat 80 mg and allopurinol. One death occurred in each febuxostat group and three in the allopurinol group.
Urate-lowering efficacy of febuxostat 80 mg exceeded that of febuxostat 40 mg and allopurinol (300/200 mg), which were comparable. In subjects with mild/moderate renal impairment, both febuxostat doses were more efficacious than allopurinol and equally safe. At the doses tested, safety of febuxostat and allopurinol was comparable.
Clinical Trial Registration
PMCID: PMC2888216  PMID: 20370912
5.  Suppression of acute proinflammatory cytokine and chemokine upregulation by post-injury administration of a novel small molecule improves long-term neurologic outcome in a mouse model of traumatic brain injury 
Traumatic brain injury (TBI) with its associated morbidity is a major area of unmet medical need that lacks effective therapies. TBI initiates a neuroinflammatory cascade characterized by activation of astrocytes and microglia, and increased production of immune mediators including proinflammatory cytokines and chemokines. This inflammatory response contributes both to the acute pathologic processes following TBI including cerebral edema, in addition to longer-term neuronal damage and cognitive impairment. However, activated glia also play a neuroprotective and reparative role in recovery from injury. Thus, potential therapeutic strategies targeting the neuroinflammatory cascade must use careful dosing considerations, such as amount of drug and timing of administration post injury, in order not to interfere with the reparative contribution of activated glia.
We tested the hypothesis that attenuation of the acute increase in proinflammatory cytokines and chemokines following TBI would decrease neurologic injury and improve functional neurologic outcome. We used the small molecule experimental therapeutic, Minozac (Mzc), to suppress TBI-induced up-regulation of glial activation and proinflammatory cytokines back towards basal levels. Mzc was administered in a clinically relevant time window post-injury in a murine closed-skull, cortical impact model of TBI. Mzc effects on the acute increase in brain cytokine and chemokine levels were measured as well as the effect on neuronal injury and neurobehavioral function.
Administration of Mzc (5 mg/kg) at 3 h and 9 h post-TBI attenuates the acute increase in proinflammatory cytokine and chemokine levels, reduces astrocyte activation, and the longer term neurologic injury, and neurobehavioral deficits measured by Y maze performance over a 28-day recovery period. Mzc-treated animals also have no significant increase in brain water content (edema), a major cause of the neurologic morbidity associated with TBI.
These results support the hypothesis that proinflammatory cytokines contribute to a glial activation cycle that produces neuronal dysfunction or injury following TBI. The improvement in long-term functional neurologic outcome following suppression of cytokine upregulation in a clinically relevant therapeutic window indicates that selective targeting of neuroinflammation may lead to novel therapies for the major neurologic morbidities resulting from head injury, and indicates the potential of Mzc as a future therapeutic for TBI.
PMCID: PMC2483713  PMID: 18590543
7.  Air Crashes and Fractured Spines 
British Medical Journal  1947;1(4491):200.
PMCID: PMC2052506  PMID: 20253727
British Medical Journal  1939;2(4121):1286-1288.
PMCID: PMC2179109  PMID: 20782880
14.  Operations on the Knee-joint* 
British Medical Journal  1937;1(3984):1015-1017.
PMCID: PMC2088781  PMID: 20780663
15.  Needles in Feet 
British Medical Journal  1936;1(3919):310.
PMCID: PMC2122396  PMID: 20779742
19.  Two Cases of Double Ureter 
Archives of Disease in Childhood  1931;6(34):231-234.
PMCID: PMC1975173  PMID: 21031850
British Medical Journal  1934;2(3838):165-166.
PMCID: PMC2447678  PMID: 20778432
British Medical Journal  1931;2(3682):177-179.
PMCID: PMC2314836  PMID: 20776308

Results 1-25 (31)