Equine fecal microbiota response to short term antibiotic administration.

Though generally safe, research continues to demonstrate negative side effects of antibiotic administration on the gastrointestinal (GIT) microbiota across species. In horses, antibiotic associated diarrhea (AAD) is a life-threatening condition linked to the GIT microbiota. This study tested the hypothesis that short term antibiotic administration to healthy horses would negatively impact the fecal microbiota as measured by their ability to digest nutrients and through fecal shedding of disease-associated-bacteria. Twenty-four horses were assigned to one of four treatment groups: control (CO); potassium penicillin/gentamicin sulfate (KPG); ceftiofur crystalline free acid (EX); trimethoprim/sulfamethoxazole (SMZ); and treated for 4 days. Fecal samples were collected before treatment began (S0), the day after treatment conclusion (S5), and at 10, 14, 21, and 28 days after initiating treatment. Horses had highly individualized responses to antibiotic administration. All horses receiving antibiotics experienced significantly softer stool compared to controls. Lactobacillus spp. were dramatically reduced in all antibiotic treated S5 samples. Horses receiving antibiotics were significantly more likely to test positive for C. difficile or C. perfringens on fecal qPCR. In conclusion, response to antibiotic administration displays high inter-individual variability, but shows changes to the functions of fecal microbiota that may depend on the antibiotic used.

Inhibition of sialidase activity and cellular invasion by the bacterial vaginosis pathogen Gardnerella vaginalis.

Bacterial vaginosis is a genital tract infection, thought to be caused by transformation of a lactobacillus-rich flora to a dysbiotic microbiota enriched in mixed anaerobes. The most prominent of these is Gardnerella vaginalis (GV), an anaerobic pathogen that produces sialidase enzyme to cleave terminal sialic acid residues from human glycans. Notably, high sialidase activity is associated with preterm birth and low birthweight. We explored the potential of the sialidase inhibitor Zanamavir against GV whole cell sialidase activity using methyl-umbelliferyl neuraminic acid (MU-NANA) cleavage assays, with Zanamavir causing a 30% reduction in whole cell GV sialidase activity (p < 0.05). Furthermore, cellular invasion assays using HeLa cervical epithelial cells, infected with GV, demonstrated that Zanamivir elicited a 50% reduction in cell association and invasion (p < 0.05). Our data thus highlight that pharmacological sialidase inhibitors are able to modify BV-associated sialidase activity and influence host-pathogen interactions and may represent novel therapeutic adjuncts.

Reducing clinical trial risk in multiple sclerosis.

OBJECTIVE: To determine the risk of clinical trial failure for new drugs in multiple sclerosis (MS) and to identify factors that could improve outcomes. METHODS: We collected data on compounds that were tested in MS from Phase I to Phase III clinical trials between 1998 and January 2015. Clinical trials success rates were calculated and compared to industry standards. The exclusion criteria for the drugs in this study were: drugs that commenced Phase I in MS prior to 1998, non-industry conducted trials, trials testing non-disease modifying drug treatment, and trials testing combinations of drugs already approved by the FDA. RESULTS: Fifty-three distinct drugs met our inclusion criteria. The cumulative success rate for MS drugs was 27%, almost triple the 10% industry rate. Clinical trial success rates in MS surpass that of industry across all phases. Phase II clinical trials completed in a "Relapsing MS" population were most successful in predicting Phase III clinical trial success. Small molecules were found to have a higher overall success rate compared to biologics; however, both drug technologies largely pursue different molecular targets. Drugs that were previously FDA approved for another indication and were subsequently tested in MS had lower success rates than drugs that had no previous FDA approval history. CONCLUSIONS: Overall, MS enjoys almost triple the clinical trial success rates of other disease areas. In addition, small molecules are superior to biologics in MS and novel drugs are superior to drugs with a previous FDA approval history outside MS.

Clinical trial success rates of anti-obesity agents: the importance of combination therapies.

The objective of this study was to construct a clinical trial profile assessing the risk of drug failure among anti-obesity agents. Research was conducted by looking at anti-obesity therapies currently on the market or in clinical trials (phases I to III) conducted from 1998 to September 2014, with the exclusion of any drugs whose phase I trial was conducted prior to January 1998. This was completed primarily through a search on http://clinicaltrials.gov where a total of 51 drugs met the search criteria. The transition probabilities were then calculated based on various classifications and compared against industry standards. The transition probability of anti-obesity agents was 8.50% whereas the transition probability of industry standards was 10.40%. Combination therapies had four times the transition probability than monotherapies, 40% and 4.75%, respectively. Therefore, it was determined that 92% of drugs fail during clinical trial testing for this indication and combination therapy appears to improve clinical trial success rates to 10-fold.

Particle size distribution and composition in a mechanically ventilated school building during air pollution episodes.

UNLABELLED: Particle count-based size distribution and PM(2.5) mass were monitored inside and outside an elementary school in Salt Lake City (UT, USA) during the winter atmospheric inversion season. The site is influenced by urban traffic and the airshed is subject to periods of high PM(2.5) concentration that is mainly submicron ammonium and nitrate. The school building has mechanical ventilation with filtration and variable-volume makeup air. Comparison of the indoor and outdoor particle size distribution on the five cleanest and five most polluted school days during the study showed that the ambient submicron particulate matter (PM) penetrated the building, but indoor concentrations were about one-eighth of outdoor levels. The indoor:outdoor PM(2.5) mass ratio averaged 0.12 and particle number ratio for sizes smaller than 1 microm averaged 0.13. The indoor submicron particle count and indoor PM(2.5) mass increased slightly during pollution episodes but remained well below outdoor levels. When the building was occupied the indoor coarse particle count was much higher than ambient levels. These results contribute to understanding the relationship between ambient monitoring station data and the actual human exposure inside institutional buildings. The study confirms that staying inside a mechanically ventilated building reduces exposure to outdoor submicron particles. PRACTICAL IMPLICATIONS: This study supports the premise that remaining inside buildings during particulate matter (PM) pollution episodes reduces exposure to submicron PM. New data on a mechanically ventilated institutional building supplements similar studies made in residences.

Comparison of central venous and external jugular venous pressures during repair of proximal femoral fracture.

BACKGROUND: External jugular venous pressure (EJVP) is a close estimate of central venous pressure (CVP) in patients undergoing mechanical ventilation in the supine position, but the effects of spontaneous respiration and posture on this relationship are not known. In this study, we compared CVP with EJVP measurements in 36 patients undergoing repair of proximal femoral fracture breathing spontaneously in the supine or lateral positions. METHODS: A standard general anaesthetic was administered with patients breathing spontaneously via a laryngeal mask airway and i.v. fluids administered according to an algorithm guided by CVP measurements. CVP and EJVP catheters were placed on the right side of the neck where possible. RESULTS: In the supine position, 185 paired measurements of CVP and EJVP and 79 in the lateral position were recorded by a blinded observer during surgery. In the supine position, the mean difference between CVP and EJVP was -0.3 mm Hg (limits of agreement -2.6 to +1.9 mm Hg, 95% confidence intervals for both upper and lower limits of agreement, respectively, were -2.9 to -2.2 and +1.6 to +2.2 mm Hg). In the lateral position, the mean difference was -1.2 mm Hg (limits of agreement -5.8 to +3.8 mm Hg, 95% confidence intervals -6.8 to -4.5 and +2.7 to +4.9 mm Hg). CONCLUSIONS: These data suggest that EJVP is an acceptable estimate of CVP in the supine position. Agreement was poor in the lateral position but was stronger for estimates of trend rather than absolute values. This could be explained by the direct effects of posture.

Comparison of external jugular and central venous pressures in mechanically ventilated patient.

We compared central venous pressures, measured via a 150 mm triple lumen catheter in the internal jugular vein with simultaneous external jugular venous pressures, measured with a 5 mm cannula in the external jugular vein, in 24 patients undergoing major surgery. Patients were mechanically ventilated in the supine position. Six sets of paired measurements of mean central venous pressure and mean external jugular venous pressure were taken by a blinded observer, in random order and at end-expiration at 30-min intervals during surgery. Four patients were not studied because of a failure to cannulate the external jugular vein. The remaining 20 patients yielded 111 sets of paired measurements. The mean difference between external jugular venous pressure and central venous pressure was 0.3 mmHg over a range of central venous pressure of 0-22 mmHg. Limits of agreement were 3.6 to +3.0 mmHg (95% CI 4.1 to +3.5 mmHg). We conclude that external jugular venous pressure is an accurate estimate of central venous pressure in surgical patients undergoing mechanical ventilation.

Effects of remifentanil and alfentanil on the cardiovascular responses to induction of anaesthesia and tracheal intubation in the elderly.

BACKGROUND: We compared the effects of remifentanil and alfentanil on arterial pressure and heart rate at induction of anaesthesia and tracheal intubation in 40 ASA I-III patients aged greater than 65 yr, in a randomized double-blind study. METHODS: Patients received either remifentanil 0.5 microg kg(-1) over 30 s, followed by an infusion of 0.1 microg kg min(-1) (group R) or alfentanil 10 microg kg(-1) over 30 s, followed by an infusion of saline (group A). Anaesthesia was then induced with propofol, rocuronium, and 1% isoflurane with 66% nitrous oxide in oxygen. RESULTS: Systolic arterial pressure (SAP) and mean arterial pressure (MAP) decreased after the induction of anaesthesia (P<0.05) and increased for 3 min after intubation in both groups (P<0.05), but remained below baseline values throughout. Heart rate remained stable after induction of anaesthesia but increased significantly from baseline after intubation for 1 and 4 min in groups R and A, respectively (P<0.05). There were no significant between-group differences in SAP, MAP, and heart rate. Diastolic pressure was significantly higher in group A than group R at 4 and 5 min after intubation (P<0.05). Hypotension (SAP < 100 mm Hg) occurred in four patients in group R and three patients in group A. CONCLUSIONS: Remifentanil and alfentanil similarly attenuate the pressor response to laryngoscopy and intubation, but the incidence of hypotension confirms that both drugs should be used with caution in elderly patients.

Induction of anesthesia in the elderly ambulatory patient: a double-blinded comparison of propofol and sevoflurane.

IMPLICATIONS: Hypotension during induction of anesthesia is common and particularly undesirable in elderly patients. This study has shown that inhaled induction with sevoflurane is well tolerated by the elderly and is associated with higher mean arterial pressure than slow propofol induction.

Comparison of effects of remifentanil and alfentanil on cardiovascular response to tracheal intubation in hypertensive patients.

In a randomized double-blind study, we compared the effect of remifentanil and alfentanil on the cardiovascular response to laryngoscopy and tracheal intubation in patients on long-term treatment for hypertension. Forty ASA II-III patients were allocated to receive (i) remifentanil 0.5 microg kg(-1) followed by an infusion of 0.1 microg kg min(-1) or (ii) alfentanil 10 microg kg(-1) followed by an infusion of saline; all patients received glycopyrrolate 200 microg before the study drug. Anaesthesia was induced with propofol and rocuronium and maintained with 1% isoflurane and 66% nitrous oxide in oxygen. Laryngoscopy and tracheal intubation were performed after establishment of neuromuscular block. Arterial pressure and heart rate (HR) were measured non-invasively at 1 min intervals from 3 min before induction until 5 min after intubation. Systolic (SAP), diastolic and mean arterial pressure decreased significantly after induction in both groups (P<0.05). Maximum increases in mean SAP after laryngoscopy and intubation were 35 and 41 mm Hg in the remifentanil and alfentanil groups, respectively. After intubation, arterial pressure did not increase above baseline values in either group. HR remained stable after induction of anaesthesia, but increased above baseline values after intubation. Mean maximum HR was 87 beats min(-1) for the remifentanil group (12 beats min(-1) above baseline; P=0.065) and 89 beats min(-1) for the alfentanil group (15 beats min(-1) above baseline; P<0.05). There were no significant differences between groups in HR or arterial pressure at any time. There were no incidences of bradycardia. Seven patients in the remifentanil group and four in the alfentanil group received ephedrine for hypotension (i.e. SAP<100 mm Hg).

Endothelium-mediated relaxation of porcine collateral-dependent arterioles is improved by exercise training.

BACKGROUND: Endothelium-dependent modulation of coronary tone is impaired in the collateral-dependent coronary microcirculation. We used a porcine model of chronic coronary occlusion and collateral development to evaluate the hypothesis that exercise training enhances endothelium-mediated relaxation and increases endothelial nitric oxide synthase (ecNOS) mRNA levels of collateral-dependent microvasculature. METHODS AND RESULTS: Adult female miniature swine were subjected to chronic, progressive ameroid occlusion of the proximal left circumflex coronary artery (LCx); after 2 months, animals were randomly exposed to 16-week exercise-training (EX group; treadmill running) or sedentary (SED group; cage confinement) protocols. After completion of EX or SED programs, coronary arterioles ( approximately 100 microm in diameter) were isolated from collateral-dependent LCx (distal to occlusion) and nonoccluded left anterior descending coronary artery (LAD) regions of each heart. Arterioles were studied by in vitro videomicroscopy or frozen for ecNOS mRNA analysis (RT-PCR techniques). Relaxation to the endothelium-dependent vasodilator bradykinin was decreased (P<0.05) in arterioles isolated from collateral-dependent LCx versus nonoccluded LAD regions of SED animals. Bradykinin-mediated relaxation, however, was not different in LCx versus LAD arterioles isolated from EX animals. Nitroprusside-induced relaxation was unaffected by either chronic occlusion or exercise. Importantly, ecNOS mRNA expression was significantly decreased in arterioles isolated from LCx versus LAD regions of SED animals. After training, ecNOS mRNA expression was not different between LAD and LCx arterioles. CONCLUSIONS: These data indicate that exercise training enhances bradykinin-mediated relaxation of collateral-dependent LCx arterioles isolated after chronic coronary occlusion, most likely because of effects on ecNOS mRNA expression and increased production of NO.

Calcium buffering in coronary smooth muscle after chronic occlusion and exercise training.

OBJECTIVE: Exercise promotes "sarcoplasmic reticulum (SR) Ca2+ unloading" in porcine coronary smooth muscle, resulting in decreased agonist-induced Ca2+ release. We studied Ca2+ handling in healthy, non-occluded right coronary artery cells from hearts chronically occluded at the circumflex artery. METHODS: Myoplasmic free Ca2+ (Ca(m)) was assessed with fura-2 in cells from sedentary (n=8) and aerobically exercise-trained (n=6) female Yucatan pigs after 6-month circumflex artery ameroid occlusion (OCC) and in cells from non-occluded, sedentary pigs (SED, n=5). First, Ca influx was induced by 80 mM KCl depolarization (priming step) followed by 5 mM caffeine to elicit maximal Ca2+ release and depletion. The SR was Ca-loaded again by depolarization and then exposed to caffeine after 2- or 11-min recovery to compare SR Ca2+ unloading. RESULTS: Baseline Ca(m), caffeine-induced peak Ca(m), and depolarization-induced maximum Ca(m) were decreased, and depolarization-induced time-to-half-maximum was increased in OCC vs. SED pigs, suggesting a tonic Ca2+ buffering (lowering) effect of occlusion. Exercise did not alter these effects. SR Ca2+ unloading occurred only in SED, as evidenced by decreased caffeine-induced Ca2+ release after 11 min of recovery, and was inhibited by low extracellular Na+. CONCLUSIONS: SR Ca2+ unloading can be demonstrated in coronary smooth muscle from sedentary pigs using a novel SR Ca2+ unloading protocol, and Ca2+ unloading partly depends on Na+-Ca2+ exchange activity. Furthermore, SR Ca2+ unloading in cells from non-occluded right coronary arteries of chronically circumflex-occluded pig hearts was not altered by exercise, perhaps due to enhanced tonic Ca2+ extrusion versus cells from normal, sedentary animals.

Sarcoplasmic reticulum Ca(2+) uptake is impaired in coronary smooth muscle distal to coronary occlusion.

After chronic occlusion, collateral-dependent coronary arteries exhibit alterations in both vasomotor reactivity and associated myoplasmic free Ca(2+) levels that are prevented by chronic exercise training. We tested the hypotheses that coronary occlusion diminishes Ca(2+) uptake by the sarcoplasmic reticulum (SR) and that exercise training would prevent impaired SR Ca(2+) uptake. Ameroid constrictors were surgically placed around the proximal left circumflex (LCx) artery of female swine 8 wk before initiating 16-wk sedentary (pen confined) or exercise-training (treadmill run) protocols. Twenty-four weeks after Ameroid placement, smooth muscles cells were enzymatically dissociated from both the LCx and nonoccluded left anterior descending (LAD) arteries of sedentary and exercise-trained pigs, and myoplasmic free Ca(2+) was studied using fura 2 microfluorometry. After the SR Ca(2+) store was partially depleted with caffeine (5 mM), KCl-induced membrane depolarization produced a significant decrease in the time to half-maximal (t(1/2)) myoplasmic free Ca(2+) accumulation in LCx versus LAD cells of sedentary pigs. Furthermore, inhibition of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA; 10 microM cyclopiazonic acid) significantly reduced t(1/2) in cells isolated from the LAD but not from the LCx. Exercise training did not prevent the differences in t(1/2) myoplasmic free Ca(2+) accumulation observed between LCx and LAD cells. Occlusion or exercise training did not alter SERCA protein levels. These results support our hypothesis of impaired SR Ca(2+) uptake in coronary smooth muscle cells isolated distal to chronic occlusion. Impaired SR Ca(2+) uptake was independent of SERCA protein levels and was not prevented by exercise training.

Endotoxin impairs agonist-stimulated intracellular free calcium (Ca(i)) responses in freshly dispersed aortic endothelial cells.

Impairment in endothelial cell intracellular free calcium (Ca(i)) mobilization mechanisms may contribute to decreased nitric oxide (NO) biosynthesis and impaired vasorelaxation responses of endotoxemic guinea pigs to endothelium-dependent vasodilators. We tested this hypothesis using fura-2 microfluorometry to compare agonist-stimulated Ca(i) responses of aortic endothelial cells freshly dispersed from guinea pigs 16 h after intraperitoneal injection of Escherichia coli endotoxin (lipopolysaccharide, LPS; 4 mg/kg) or saline (CON). In the presence of normal extracellular Ca2+ (2 mmol/L), basal (non-stimulated) endothelial Ca(i) (340/380 nm fluorescence ratio, R) was not different between CON and LPS cells (1.1 +/- 0.03 and 1.1 +/- 0.03, respectively). However, exposure to ADP (10 micromol/L) produced a biphasic increase in Ca(i) that was markedly decreased in cells from LPS-treated animals (P < 0.0001). Peak ADP-stimulated Ca(i) responses averaged 2.2 +/- 0.21 in CON cells and 1.5 +/- 0.11 (P < 0.01) in cells dispersed from LPS-treated animals. Exposure to acetylcholine (ACh; 10 micromol/L) produced sustained increases in Ca(i) (R = 1.4 +/- 0.13) in CON cells; however, LPS abolished Ca(i) responses to ACh. Exposure of endothelial cells to substance P (100 nmol/L) produced a biphasic increase in Ca(i) that was not different between groups. In the absence of extracellular Ca2+ (plus 10 micromol/L EGTA), exposure to ADP (10 micromol/L) produced transient increases in Ca(i) (Ca2+ release) that were decreased in cells from LPS-treated versus CON animals. Exposure to ACh in zero Ca2+ (10 micromol/L) produced smaller increases in Ca(i) (peak R = 1.3 +/- 0.12) in CON cells (when compared to ADP); however, Ca(i) responses to ACh remained absent in cells from LPS-treated animals. Re-exposure to Ca2+ produced sustained ACh-induced Ca(i) responses (Ca2+ influx) in cells from CON, but not LPS-treated animals; LPS markedly impaired (P< 0.05) ADP-induced sustained Ca(i) responses. Our data demonstrate that in vivo LPS exposure elicits decreased agonist-stimulated endothelial Ca(i) responses primarily involving impaired Ca2+ influx mechanisms. Known dependence of endothelial agonist-stimulated NO synthesis on Ca(i) suggests that defects in cell Ca2+ mobilization may contribute to LPS-induced impaired NO biosynthesis and decreased endothelium-dependent relaxation.

Enhanced L-type Ca2+ channel current density in coronary smooth muscle of exercise-trained pigs is compensated to limit myoplasmic free Ca2+ accumulation.

We hypothesized that enhanced voltage-gated Ca2+ channel current (VGCC) density in coronary smooth muscle cells of exercise-trained miniature Yucatan pigs is compensated by other cellular Ca2+ regulatory mechanisms to limit net myoplasmic free Ca2+ accumulation. Whole-cell voltage clamp experiments demonstrated enhanced VGCC density in smooth muscle cells freshly dispersed from coronary arteries of exercise-trained vs. sedentary animals. In separate experiments using fura-2 microfluorometry, we measured depolarization-induced (80 mM KCl) accumulation of myoplasmic free Ba2+ and free Ca2+. Both maximal rate and net accumulation of free Ba2+ in response to membrane depolarization were increased in smooth muscle cells isolated from exercise-trained pigs, consistent with an increased VGCC density. Depolarization also produced an enhanced maximal rate of free Ca2+ accumulation in cells of exercise-trained pigs; however, net accumulation of free Ca2+ was not significantly increased suggesting enhanced Ca2+ influx was compensated to limit net free Ca2+ accumulation. Inhibition of sarco-endoplasmic reticulum Ca2+-transporting ATPase (SERCA; 10 microM cyclopiazonic acid) and/or sarcolemmal Na+-Ca2+ exchange (low extracellular Na+) suggested neither mechanism compensated the enhanced VGCC in cells of exercise-trained animals. Local Ca2+-dependent inactivation of VGCC, assessed by buffering myoplasmic Ca2+ with EGTA in the pipette and using Ca2+ and Ba2+ as charge carriers, was not different between cells of sedentary and exercise-trained animals. Our findings indicate that increased VGCC density is compensated by other cellular Ca2+ regulatory mechanisms to limit net myoplasmic free Ca2+ accumulation in smooth muscle cells of exercise-trained animals. Further, SERCA, Na+-Ca2+ exchange and local Ca2+-dependent inactivation of VGCC do not appear to function as compensatory mechanisms. Additional potential compensatory mechanisms include Ca2+ extrusion via plasma membrane Ca2+-ATPase, mitochondrial uptake, myoplasmic Ca2+-binding proteins and other sources of VGCC inactivation.

Exercise training restores adenosine-induced relaxation in coronary arteries distal to chronic occlusion.

We previously reported that canine collateral-dependent coronary arteries exhibit impaired relaxation to adenosine but not sodium nitroprusside. In contrast, exercise training enhances adenosine sensitivity of normal porcine coronary arteries. These results stimulated the hypothesis that chronic coronary occlusion and exercise training produce differential effects on cAMP- versus cGMP-mediated relaxation. To test this hypothesis, Ameroid occluders were surgically placed around the proximal left circumflex coronary artery (LCx) of female Yucatan miniature swine 8 wk before initiating sedentary or exercise training (treadmill run, 16 wk) protocols. Relaxation to the cAMP-dependent vasodilators adenosine (10(-7) to 10(-3) M) and isoproterenol (3 x 10(-8) to 3 x 10(-5) M) were impaired in collateral-dependent LCx versus nonoccluded left anterior descending (LAD) arterial rings isolated from sedentary but not exercise-trained pigs. Furthermore, adenosine-mediated reductions in simultaneous tension and myoplasmic free Ca(2+) were impaired in LCx versus LAD arteries isolated from sedentary but not exercise-trained pigs. In contrast, relaxation in response to the cAMP-dependent vasodilator forskolin (10(-9) to 10(-5) M) and the cGMP-dependent vasodilator sodium nitroprusside (10(-9) to 10(-4) M) was not different in LCx versus LAD arteries of sedentary or exercise-trained animals. These data suggest that chronic occlusion impairs receptor-dependent, cAMP-mediated relaxation; receptor-independent cAMP- and cGMP-mediated relaxation were unimpaired. Importantly, exercise training restores cAMP-mediated relaxation of collateral-dependent coronary arteries.

Chronic exercise training improves ACh-induced vasorelaxation in pulmonary arteries of pigs.

We hypothesized that exercise training would lead to enhanced endothelium-dependent vasodilation in porcine pulmonary arteries. Pulmonary artery rings (2- to 3-mm OD) were obtained from female Yucatan miniature swine with surgically induced coronary artery occlusion (ameroid occluder). Exercise training was performed for 16 wk, and vasomotor responses were studied by using standard isometric techniques. Contractile responses to 80 mM KCl, isosmotic KCl (10-100 mM), and norepinephrine (10(-8) to 10(-4) M) did not differ between sedentary (Sed) and exercise-trained (Ex) pigs. Relaxation was assessed to endothelium-dependent and endothelium-independent vasodilators after norepinephrine contraction. Pulmonary arteries of Ex pigs exhibited greater maximal relaxation to ACh (61.9 +/- 3.5%) than did those of Sed pigs (52.3 +/- 3.9%; P < 0.05). Endothelium-independent relaxation to sodium nitroprusside did not differ. Inhibition of nitric oxide synthase significantly decreased acetylcholine-induced relaxation, with greater inhibition in arteries from Ex pigs (P < 0.05). Inhibition of cyclooxygenase enhanced relaxation to acetylcholine in arteries from Sed pigs. We conclude that exercise training enhances endothelium-dependent (ACh-mediated) vasorelaxation in pulmonary arteries by mechanisms of increased reliance on nitric oxide and reduced production of a prostanoid constrictor.

The new millennium brings nursing informatics into the OR.

Will the perioperative arena step out of the dark ages and into the new millennium with informatics? A paradigm shift must occur in both the perioperative arena and health care organizations. Health care organizations must realize the value of informatics and the importance of integrating the informatics nurse into the organizational information system's team. This article discusses how the informatics nurse can accelerate the paradigm shift in the perioperative arena if given the opportunity. The informatics nurse's proactive involvement in the perioperative environment will ensure that information handling technologies benefit the perioperative specialty and, ultimately, enhance patient care.

Dyslipidemia and vascular dysfunction in diabetic pigs fed an atherogenic diet.

Diabetic patients typically have not only hyperglycemia but also dyslipidemia. Study of the pathogenic components of the diabetic milieu and mechanisms of accelerated atherosclerosis is hindered by inadequate animal models. A potentially suitable animal model for human diabetic dyslipidemia is the pig, because it carries a large fraction of total cholesterol in low-density lipoprotein (LDL), similar to humans. In this study, male Sinclair miniature pigs were made diabetic by destroying the insulin-producing cells of the pancreas with alloxan and then were fed a high fat and high cholesterol diet for comparison with pigs fed a nondiabetic high fat and high cholesterol diet and control pigs. Diabetic pigs exhibited hyperglycemia, but plasma urea nitrogen, creatinine, and transaminase levels were in the normal range, indicating no adverse effects on kidney and liver function. The lipoprotein profile in diabetic pigs was similar to that found in human diabetic patients and was characterized by hypertriglyceridemia (2.8-fold increase versus control and high fat-fed pigs) and a profound shift of cholesterol distribution into the LDL fraction (81%) versus the distribution in high fat-fed (64%) and control (57%) pigs. LDL particles were lipid-enriched and more heterogeneous in diabetic pigs. Apolipoprotein B was distributed among a much broader spectrum of LDL particles, and apolipoprotein E was partially redistributed from high-density lipoprotein to apolipoprotein B-containing lipoproteins in diabetic pigs. There was little change in apolipoprotein A-I distribution. Diabetic pigs showed several early signs of excess vascular disease. In diabetic pigs, 75% of the coronary artery segments showed contractile oscillations in response to prostaglandin F(2alpha) compared with 25% in high fat-fed pigs and 10% in control pigs. Endothelium-dependent relaxation of brachial arteries was nearly abolished in diabetic pigs but unchanged in high fat-fed versus control pigs. Carotid artery Sudan IV staining for fatty streaks was significantly increased only in diabetic pigs. This porcine model should provide insights into the etiology of human diabetic dyslipidemia and facilitate study of peripheral vascular and coronary artery disease in diabetic patients.