Mexiletine-quinidine combination: Electrophysiologic correlates of a favorable antiarrhythmic interaction in humans

Combination therapy with mexiletine and quinidine has been shown to be more effective than either agent alone. The ability of mexiletine monotherapy, quinidine monotherapy and mexiletine-quinidine combination therapy to suppress inducible sustained ventricular tachycardia was related to drug-induced changes in ventricular refractoriness, conduction times and monophasic action potential duration recorded from both ventricles. Ventricular tachycardia could no longer be induced in 7 (35%) of the 20 patients studied with combination therapy. This was a significantly higher proportion of patients than that of the groups responding to either monotherapy (quinidine, 10%; mexiletine, 5%).Ventricular effective and functional refractory periods were measured when applying single (S2), double (S3) and triple (S4) extrastimuli. Quinidine monotherapy increased functional and effective refractory periods of both single and multiple extrastimuli. However, when comparing measurements made during mexiletine treatment with those at baseline, mexiletine monotherapy increased only the refractory periods of S4. The effective refractory period of S4 during mexiletine monotherapy (200 ± 20 ins) was significantly longer than at baseline (160 ± 21 ms). Similarly, when comparing measurements made during combination therapy with those during quinidine monotherapy, combination therapy significantly increased the refractory periods only of multiple extrastimuli. The effective refractory period of S4 during combination therapy (253 ± 26 ms) was significantly longer than that of quinidine monotherapy (223 ± 27 ms). The only other significant difference between combination therapy and monotherapy with either agent was a greater prolongation of conduction time to the left ventricular dyskinetic zone with combination therapy.Therefore, mexiletine-quinidine combination therapy is associated with additional prolongation of the refractory periods of multiple extrastimuli and with further prolongation of conduction into the dyskinetic zone of the left ventricle. These electrophysiologic effects may be markers of enhanced antiarrhythmic activity

Large Area Mapping at 850 Microns. IV. Analysis of the Clump Distribution in the Orion B South Molecular Cloud

We present results from a survey of a 1300 arcmin^2 region of the Orion B South molecular cloud, including NGC 2024, NGC 2023, and the Horsehead Nebula (B33), obtained using the Submillimetre Common-User Bolometer Array (SCUBA) on the James Clerk Maxwell Telescope. Submillimeter continuum observations at 450 microns and 850 microns are discussed. Using an automated algorithm, 57 discrete emission features (``clumps'') are identified in the 850 micron map. The physical conditions within these clumps are investigated under the assumption that the objects are in quasi-hydrostatic equilibrium. The best fit dust temperature for the clumps is found to be T_d = 18 +/- 4 K, with the exception of those associated with the few known far infrared sources residing in NGC 2024. The latter internally heated sources are found to be much warmer. In the region surrounding NGC 2023, the clump dust temperatures agree with clump gas temperatures determined from molecular line excitation measurements of the CO molecule. The bounding pressure on the clumps lies in the range log(k^-1 P cm^3 K^-1) = 6.1 +/- 0.3. The cumulative mass distribution is steep at the high mass end, as is the stellar Initial Mass Function. The distribution flattens significantly at lower masses, with a turn-over around 3 -- 10 M_sun.Comment: 41 pages, 16 figures, accepted by Ap

Delayed onset of changes in soma action potential genesis in nociceptive A-beta DRG neurons in vivo in a rat model of osteoarthritis

<p>Abstract</p> <p>Background</p> <p>Clinical data on osteoarthritis (OA) suggest widespread changes in sensory function that vary during the progression of OA. In previous studies on a surgically-induced animal model of OA we have observed that changes in structure and gene expression follow a variable trajectory over the initial days and weeks. To investigate mechanisms underlying changes in sensory function in this model, the present electrophysiological study compared properties of primary sensory nociceptive neurons at one and two months after model induction with properties in naïve control animals. Pilot data indicated no difference in C- or Aδ-fiber associated neurons and therefore the focus is on Aβ-fiber nociceptive neurons.</p> <p>Results</p> <p>At one month after unilateral derangement of the knee by cutting the anterior cruciate ligament and removing the medial meniscus, the only changes observed in Aβ-fiber dorsal root ganglion (DRG) neurons were in nociceptor-like unresponsive neurons bearing a hump on the repolarization phase; these changes consisted of longer half width, reflecting slowed dynamics of AP genesis, a depolarized Vm and an increased AP amplitude. At two months, changes observed were in Aβ-fiber high threshold mechanoreceptors, which exhibited shorter AP duration at base and half width, shorter rise time and fall time, and faster maximum rising rate/maximum falling rate, reflecting accelerated dynamics of AP genesis.</p> <p>Conclusion</p> <p>These data indicate that Aβ nociceptive neurons undergo significant changes that vary in time and occur later than changes in structure and in nociceptive scores in this surgically induced OA model. Thus, if changes in Aβ-fiber nociceptive neurons in this model reflect a role in OA pain, they may relate to mechanisms underlying pain associated with advanced OA.</p

Racial differences in renal allograft survival: The role of systemic hypertension

Racial differences in renal allograft survival: The role of systemic hypertension. The rate of decline in the number of functioning renal allografts beyond the first year after transplantation has changed little in the last 25 years, and during long-term follow-up most allografts are lost due to chronic transplant rejection or patient death. The recipient race correlates with allograft survival, and African American recipients have a lower allograft survival than Caucasians. The goal of the present study was to identify clinical variables present during the first six months after transplantation that predict the loss of renal allografts beyond six months after transplantation, and in particular to determine the role of systemic hypertension on renal allograft survival in black and white recipients. This study includes 547 recipients of first cadaveric renal allografts performed at The Ohio State University. All patients were treated with a uniform immunosuppressive protocol and had a follow-up of at least three years. By multivariate analysis the following variables correlate with poor allograft survival: an elevated serum creatinine concentration measured six months after transplantation (SCr6mo) (P < 0.0001); black race (P < 0.0001); increasing numbers of acute rejection episodes (ATR) (P = 0.002); and young recipients (P = 0.026). Allograft survival is significantly worse in black (mean allograft half-life of 7.7 ± 1.3 years) than in white recipients (24 ± 3 years) (P < 0.0001). Black recipients also have a significantly higher six month average mean arterial blood pressure (MAP) (105 ± 8 mm Hg) than white recipients (102 ± 7 mm Hg) (P = 0.002). However, the prevalence of hypertension is not significantly different in black (33%) than in white recipients (26%). Furthermore, increasing MAP levels correlate with a shorter allograft half-life in black recipients (P = 0.0002), but not in white recipients (P = 0.84). Allograft survival was eight times shorter in hypertensive black (3.1 ± 0.7 years) than in hypertensive white recipients (24.6 ± 7 years). In contrast, allograft survival was not statistically different between normotensive black and white patients. In conclusion, the presence of poorly controlled systemic hypertension, early after renal transplantation, correlates with poor allograft survival in black recipients. Thus, systemic hypertension may explain, in part, differences in renal allograft survival between black and white patients

Metabotropic glutamate antagonists alone and in combination with morphine: comparison across two models of acute pain and a model of persistent, inflammatory pain

The present study examined the effects of the mGluR1 antagonist JNJ16259685 (JNJ) and the mGluR5 antagonist MPEP alone and in combination with morphine in two acute pain models (hotplate, warm water tail-withdrawal), and a persistent, inflammatory pain model (capsaicin). In the hotplate and warm water tail-withdrawal procedures, JNJ and MPEP were ineffective when administered alone. In both procedures, JNJ potentiated morphine antinociception. In the hot plate procedure, MPEP potentiated morphine antinociception at the highest dose examined, whereas in the warm water tail-withdrawal procedure MPEP attenuated morphine antinociception at a moderate dose and potentiated morphine antinociception at a high dose. For both JNJ and MPEP, the magnitude of this morphine potentiation was considerably greater in the hotplate procedure. In the capsaicin procedure, the highest dose of MPEP produced intermediate levels of antihyperalgesia and also attenuated the effects of a dose of morphine that produced intermediate levels of antihyperalgesia. In contrast, JNJ had no effect when administered alone in the capsaicin procedure and did not alter morphine-induced antihyperalgesia. The present findings suggest that the effects produced by mGluR1 and mGluR5 antagonists alone and in combination with morphine can be differentiated in models of both acute and persistent pain

Quinidine pharmacodynamics in patients with arrhythmia: Effects of left ventricular function

Objectives.This study was undertaken to determine whether quinidine pharmacodynamics are altered in the presence of left ventricular dysfunction.Background.Left ventricular function is an independent predictor of antiarrhythmic drug efficacy. However, the effects of left ventricular dysfunction on the pharmacodynamics of antiarrhythmic drugs have not been studied extensively.Methods.Signal-averaged electrocardiograms were obtained and quinidine plasma concentrations measured during 24-h quinidine washout in 22 patients.Results.Linear quinidine concentration-effect relations were observed for QRS and QT intervals corrected for heart rate. The slopes of the concentration-effect relation describing changes in the corrected QT (QTc) interval were significantly higher in the group with left ventricular ejection fraction ≥0.35 ([mean ±SD] 29.5 ± 11.2 ms/μg per ml) than in the group with a low left ventricular ejection fraction (15.7 ± 9.7 ms/μg per ml, p = 0.001). The QRS concentration-effect relations were not different in the two groups. A significant linear correlation was observed between the slopes of the concentration-effect relations describing changes in QTc intervals and left ventricular ejection fraction (r = 0.7, p < 0.001). Nineteen patients with inducible ventricular tachycardia underwent serial electrophysiologic studies for evaluation of quinidine efficacy. Ventricular tachycardia could not be induced during quinidine therapy in eight patients. The slopes of the quinidine concentration-effect relations for QTc intervals were significantly higher in quinidine responders than in nonresponders (p < 0.05).Conclusions.The effects of quinidine on ventricular repolarization are linearly related to left ventricular ejection fraction. Quinidine concentration-effect relations describing ventricular repolarization are associated with antiarrhythmic efficacy in patients with ventricular tachycardia

Structure of the first representative of Pfam family PF04016 (DUF364) reveals enolase and Rossmann-like folds that combine to form a unique active site with a possible role in heavy-metal chelation.

The crystal structure of Dhaf4260 from Desulfitobacterium hafniense DCB-2 was determined by single-wavelength anomalous diffraction (SAD) to a resolution of 2.01 Å using the semi-automated high-throughput pipeline of the Joint Center for Structural Genomics (JCSG) as part of the NIGMS Protein Structure Initiative (PSI). This protein structure is the first representative of the PF04016 (DUF364) Pfam family and reveals a novel combination of two well known domains (an enolase N-terminal-like fold followed by a Rossmann-like domain). Structural and bioinformatic analyses reveal partial similarities to Rossmann-like methyltransferases, with residues from the enolase-like fold combining to form a unique active site that is likely to be involved in the condensation or hydrolysis of molecules implicated in the synthesis of flavins, pterins or other siderophores. The genome context of Dhaf4260 and homologs additionally supports a role in heavy-metal chelation

Implications of zero-deforestation commitments: forest quality and hunting pressure limit mammal persistence in fragmented tropical landscapes

Zero-deforestation commitments seek to decouple agricultural production and forest loss to improve prospects for biodiversity. However, the effectiveness of methods designed to meet these commitments is poorly understood. In a highly-fragmented tropical landscape dominated by oil palm, we tested the capacity for the High Carbon Stock (HCS) Approach to prioritise forest remnants that sustain mammal diversity. Patches afforded High Priority by HCS protocols (100 ha core area) provided important refuges for IUCN-threatened species and megafauna. However, patch-scale HCS area recommendations conserved only 35% of the mammal community. At least 3,000 ha would be required to retain intact mammal assemblages, with nearly ten times this area needed if hunting pressure was high. While current HCS protocols will safeguard patches capable of sustaining biodiversity, highly-fragmented tropical landscapes typical of zero-deforestation pledges will require thinking beyond the patch, towards strategically configured forest remnants at the landscape-level and enforcing strict controls on hunting

The Lantern Vol. 41, No. 1, Fall 1974

• The Fable • Landscape - Clear Weather in the Valley • Josephine Palooka • Don\u27t Bark Twice - It\u27s All Right • Masks • Suicide Note From a Lemming • The Death of Dame Sexton • Come September • Leaves • Spruce Grove • The Class of \u2775 • The Promise • Images • Sixth Station • Borealis • To Gemhttps://digitalcommons.ursinus.edu/lantern/1105/thumbnail.jp

Structure of a putative NTP pyrophosphohydrolase: YP_001813558.1 from Exiguobacterium sibiricum 255-15.

The crystal structure of a putative NTPase, YP_001813558.1 from Exiguobacterium sibiricum 255-15 (PF09934, DUF2166) was determined to 1.78 Å resolution. YP_001813558.1 and its homologs (dimeric dUTPases, MazG proteins and HisE-encoded phosphoribosyl ATP pyrophosphohydrolases) form a superfamily of all-α-helical NTP pyrophosphatases. In dimeric dUTPase-like proteins, a central four-helix bundle forms the active site. However, in YP_001813558.1, an unexpected intertwined swapping of two of the helices that compose the conserved helix bundle results in a `linked dimer' that has not previously been observed for this family. Interestingly, despite this novel mode of dimerization, the metal-binding site for divalent cations, such as magnesium, that are essential for NTPase activity is still conserved. Furthermore, the active-site residues that are involved in sugar binding of the NTPs are also conserved when compared with other α-helical NTPases, but those that recognize the nucleotide bases are not conserved, suggesting a different substrate specificity