Use of an in vitro flat-bed biofilm model to measure biologically active anti-odour compounds.

The objective of this study was to demonstrate the utility of a modified flat-bed perfusion biofilm matrix system for testing toothpaste formulations directly, without dilution, as a layer in direct contact with the biofilm matrix surface. Final biofilm yields and volatile sulphur compounds (VSC) biogenesis were measured to show the relative efficacy of toothpaste formulations. Diffusion characteristics of the flat-bed system to exposure with Meridol® tooth and tongue gel (TTG; 1,400 ppm F(-) from amine fluoride/stannous fluoride, 0.5 % zinc lactate, oral malodour counteractives) was assessed using a bioluminescent target species Escherichia coli Nissle 1917/pGLITE coupled with a low-light photon camera to visualise the kill kinetics. Tongue-flora derived, mixed culture biofilms (n = 4) received 5, 15 and 30 min treatment with TTG, respectively, to determine the optimum time of exposure. VSC biogenesis was measured from headspace samples by gas chromatography prior to and following treatment of two daily applications for 4 days of treatment (TTG), positive control (CHX gel) and negative controls (placebo and sham treatment). Viable counts were performed at the end of experiments by destructive sampling of the biofilms and plating onto selective and non-selective agar. Following a single treatment with TTG, the E. coli biofilm with lux target gave >50 % reduction of luminescence within 2 to 3 h before recovering to a steady state over 10 h, suggesting biofilm cidal activity rather biostasis. For mixed culture biofilms, 15- and 30-min treatment exposure with TTG gave almost identical reductions in final biofilm yields. For comparing efficacy of treatments, biofilms treated with TTG gave greatest reductions in both pre-post levels of H2S (P < 0.01) and CH3SH (P < 0.05) and population yields at the end of the experiments (P < 0.001) compared to placebo and positive control. The in vitro flat-bed perfusion model may be used to replicate many of the activities and reactions believed to be occurring by the tongue biofilm microflora within a real mouth, including VSC biogenesis and its inhibition by exposure to active agents as components of toothpastes and gels applied in direct contact with the biofilm.

Eight-week, placebo-controlled, double-blind comparison of the antidepressant efficacy and tolerability of bupropion XR and venlafaxine XR.

The efficacy, safety and tolerability of bupropion XR and venlafaxine XR was assessed and compared with placebo in adult outpatients with major depressive disorder (MDD). Adults meeting DSM-IV criteria for MDD with a minimum Hamilton Depression Rating Scale (HAMD) 17-Item total score of > or =18 were randomized to eight weeks of double-blind treatment with either bupropion XR (150 mg/day), venlafaxine XR (75 mg/day) or placebo. At the end of the fourth week of treatment, a dosage increase to bupropion XR 300 mg/day or venlafaxine XR 150 mg/day was allowed if, in the opinion of the investigator, response was inadequate. The primary efficacy endpoint was mean change from baseline at week 8 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score last observation carried forward (LOCF). Mean changes from baseline at week 8 (LOCF) in MADRS total score were statistically significant for bupropion XR and venlafaxine XR patients compared to the placebo group: -16.0 for bupropion XR (P = 0.006 vs placebo), -17.1 for venlafaxine XR (P < 0.001 vs placebo) and -13.5 for placebo. Secondary outcomes (including CGI-S, HAM-A, MEI, Q-LES-Q-SF, responder and remitter analyses) also improved significantly for both active treatment groups compared with placebo. The most frequently reported adverse events were dry mouth and insomnia for bupropion XR, and nausea, hyperhidrosis, fatigue, and insomnia for venlafaxine XR. In this double-blind, placebo-controlled trial, bupropion XR at doses up to 300 mg/day and venlafaxine XR at doses up to 150 mg/day demonstrated comparable antidepressant efficacy.

Daily reduction of oral malodor with the use of a sonic tongue brush combined with an antibacterial tongue spray in a randomized cross-over clinical investigation.

The objective of this clinical investigation was to test the effectiveness on breath odor of a newly designed sonic tongue brush (TongueCare+, TC). It consists of a soft silicone brush optimally designed based on the tongue's anatomy to remove bacterial biofilm from the tongue's complex surface, and it is coupled with a sonic power toothbrush handle. TC was used in combination with an antibacterial tongue spray (BreathRx, BRx) containing 0.09% cetylpyridinium chloride and 0.7% zinc gluconate. A total of 21 participants with oral malodor exceeding the threshold for recognition took part in this cross-over clinical investigation, which consisted of a single use of four treatment arms with one week washout period in between. The treatments consisted of: (1) TC + BRx, (2) TC + water, (3) BRx and (4) water. Malodor levels and bacterial density were monitored up to 6 h by organoleptic scoring and selective plating, respectively. The organoleptic score and bacterial density were significantly lower after using TC + BRx compared to all alternative treatments at all time points. A significant decrease in both parameters was detected after a single use of TC + BRx, from levels characteristic of high oral malodor, to barely noticeable levels after treatment and this was maintained up to 6 h. Moreover, we identified a significant positive correlation between bacterial density and organoleptic score, confirming that bacterial tongue biofilm is the root cause of oral malodor in these subjects. The results of this clinical investigation demonstrated that the combined treatment of a sonic tongue brush with the antibacterial tongue spray is able to deliver more than 6 h of fresh breath following a single use. The clinical investigation was registered at the ISRCTN registry under study identification number ISRCTN38199132.

Educational, occupational, and insurance status of childhood cancer survivors in their fourth and fifth decades of life.

PURPOSE: Survivors of childhood cancer who are now greater than or equal to 30 years of age are available for study in significant numbers for the first time. An evaluation of their educational achievement, current employment status, frequency of problems in the work-place, and ability to obtain affordable health and life insurance was the aim of this study. PATIENTS AND METHODS: This was a case-control study of 219 childhood cancer survivors with individually matched controls from two tertiary-care pediatric centers. Telephone interviews were used and drew on a 356-item basic instrument for both subjects and controls. Medical (including intensity of therapy), marital, and psychosocial areas were included in the survey, but statistical comparisons concentrated on educational and economic issues. RESULTS: The overall current status of survivors and controls in the relevant areas, ie, education, employment, and insurance, was similar. A history of employment discrimination for entry into the uniformed services and in other special situations, and life insurance discrimination during the initial years after the completion of therapy was noted. Survivors experienced few problems in the work-place. Survivors of CNS tumors were unique, with problems in many of the areas studied, although there were notable individual exceptions. CONCLUSION: With the exception of those individuals with CNS tumor histories, survivors who were treated in the era of 1945 to 1975 had few economic sequelae of cancer or its therapy that extended beyond the first decades after treatment.

Changes in L-type calcium channel abundance and function during the transition to pacing-induced congestive heart failure.

OBJECTIVE: The development of congestive heart failure (CHF) is accompanied by left ventricular (LV) and myocyte contractile dysfunction. However, time-dependent cellular and ionic events which contribute to the initiation and progression of CHF remain unclear. This study tested the central hypothesis that changes in L-type Ca2+ channel current (ICa) and abundance (Bmax) are early events in the transition to CHF. METHODS: LV fractional shortening by echocardiography, isolated LV myocyte shortening velocity by videomicroscopy, ICa by voltage-clamp, and Bmax by [3H]nitrendipine binding were determined at each week during the progression of pacing-induced CHF in pigs (240 bpm; n = 6/week for 3 weeks). Myocyte and L-type Ca2+ channel function were determined under basal conditions and after beta-adrenergic receptor stimulation with 25 nM isoproterenol. RESULTS: After 1 week of pacing, myocyte and L-type Ca2+ current responses to beta-adrenergic receptor stimulation were reduced by 20% from control values and was accompanied by over a 210% increase in plasma catecholamine levels. After 2 weeks of pacing, reductions in LV fractional shortening and myocyte shortening velocity from control values (20 +/- 1 vs. 34 +/- 2% and 36.7 +/- 2.9 vs. 50.6 +/- 2.4 microns/s, respectively, P < 0.05) were paralleled by decreased ICa (2.47 +/- 0.10 vs. 3.63 +/- 0.25 pA/pF, P < 0.02) and Bmax (149 +/- 16 vs. 180 +/- 12 fmol/mg, P < 0.03). After 3 weeks of pacing, LV fractional shortening was reduced by over 50%, myocyte shortening velocity by 37%, and ICa and Bmax were reduced by over 25% from control values. Furthermore, after 3 weeks of pacing, the ICa/Bmax ratio was reduced from control values (16.2 +/- 0.9 vs. 20.6 +/- 1.2 [fA/pF]/[fmol/mg], P < 0.03), which suggests functional defects in the remaining L-type Ca2+ channels. CONCLUSIONS: An early event during the transition to pacing-induced CHF was diminished beta-adrenergic receptor augmented L-type Ca2+ current, which was followed by an absolute loss of steady-state L-type Ca2+ current and channel abundance. The development of severe CHF was accompanied by a loss of Ca2+ carrying capacity through residual channels. These unique findings suggest that a contributory molecular mechanism for the initiation and progression of CHF is changes in the structure and function of the L-type Ca2+ channels.

The rate and anisotropy of impulse propagation in the postnatal terminal crest are correlated with remodeling of Cx43 gap junction pattern.

BACKGROUND: Disruptions to intermyocyte coupling have been implicated in arrhythmogenesis and development of conduction disturbances. At present, understanding of the relationship between the microscopic organization of intercellular coupling and the macroscopic spread of impulse in the normal and diseased heart is largely confined to theoretical analyses. METHODS AND RESULTS: The abundance and arrangement of gap junctions, as well as conduction properties, were assessed in terminal crest preparations isolated from the atria of neonate, weanling, and adult rabbits. We report that the connexin composition of terminal crest was uncomplicated, with Cx43 being the most prominent isoform detectable by Western blotting and immunostaining. Terminal crest myocytes showed little change in total Cx43-gap junction per cell during postnatal growth as assessed by stereology. However, marked non-uniformities emerged in the sarcolemmal distribution of Cx43-gap junctions. Cx43-gap junction area at myocyte termini increased 3.5-fold from birth to adulthood. Correlated with this change in Cx43, impulse propagation velocity parallel to the myofiber axis, as assessed by multi-site optical mapping using voltage-sensitive dye (di-4-ANEPPS), increased 2.4-fold. Conversely, the amount of Cx43-gap junctions on myocyte sides, and the conduction velocity transverse to the myofiber axis, remained relatively invariant during maturation. Hence, the increasing electrical anisotropy of maturing terminal crest was wholly accounted for by increases in conductance velocity along the bundle. This increase in longitudinal conduction velocity was correlated with changes in the sarcolemmal pattern, but not the overall density, of Cx43-gap junctions. CONCLUSIONS: This study provides the first correlative structure/function analysis of the relationship between the macroscopic conduction of impulse and the microscopic cellular organization of gap junctions in a differentiating cardiac bundle. Confirmation is provided for theoretical predictions which emphasize the importance of the cell-to-cell geometry of coupling in determining the spread and pattern of myocardial activation.

Rimcazole analogs attenuate the convulsive effects of cocaine: correlation with binding to sigma receptors rather than dopamine transporters.

Cocaine interacts with dopamine transporters and sigma receptors at concentrations that are achievable in vivo, suggesting that they may both be viable targets for the development of anti-cocaine agents. Rimcazole binds to both of these targets and also attenuates cocaine-induced locomotor activity and sensitization. To further characterize the mechanism(s) underlying the attenuation of cocaine-induced convulsions and lethality, rimcazole and three analogs (SH3/24, SH2/21, SH1/57), with a range of affinities for dopamine transporters and sigma receptors, were evaluated. The highly selective and potent sigma receptor ligand LR176 was used as a reference. Competition binding studies confirmed that the rank order of the compounds at dopamine transporters vs. sigma receptors differed, thus enabling a correlation between the relative anti-cocaine activities of the compounds in behavioral studies and their affinities for dopamine transporters vs. sigma receptors. In behavioral studies, male Swiss Webster mice were pre-treated with one of the compounds (0-60 mg/kg, i.p.), then challenged 15 min later with either a convulsive (60 mg/kg, i.p.) or lethal (125 mg/kg, i.p.) dose of cocaine. When the compounds were ranked according to their protective effect, there was a significant correlation between their anticonvulsant actions and their affinities for sigma receptors, but not dopamine transporters. Although the rimcazole analogs were ineffective against the lethal effects of cocaine, the selective sigma receptor ligand LR176 provided significant protection. These data thus suggest that sigma receptors may mediate some of the toxic effects associated with cocaine and that sigma receptor antagonists may be developed as pharmacotherapeutic agents for this application.

The direct effects of protamine sulfate on myocyte contractile processes.

The use of protamine sulfate in patients has been associated with circulatory collapse and is suspected to directly depress left ventricular function. However, the cellular basis for these changes that occur after protamine administration are unknown. Accordingly, the first objective of this study was to determine the direct effects of protamine on isolated myocyte contractile function. Myocytes were isolated from porcine hearts and contractile function was examined at baseline and then after the administration of protamine in concentrations of 20, 40, or 80 micrograms/ml. These concentrations were chosen because they reflect the serum concentrations of protamine commonly obtained in patients. The presence of protamine resulted in a dose-dependent decline in myocyte contractile function. For example, in the presence of a 20 microgram/ml concentration of protamine myocyte contractile function did not change significantly from baseline values, whereas an 80 microgram/ml protamine concentration caused myocyte percent and velocity of shortening to fall by more than 35% from baseline values. In light of the fact that protamine directly depressed myocyte contractile function, a second objective of this study was to examine potential cellular mechanisms responsible for this effect. Accordingly, in the next series of experiments, the effects of protamine on the myocyte sarcolemmal beta-adrenergic receptor system were examined by measuring myocyte contractile function with the beta-adrenergic agonist isoproterenol (25 nmol/L), as well as with the concomitant addition of protamine and isoproterenol. In the presence of protamine, myocyte beta-adrenergic responsiveness was significantly reduced. For example, in the presence of an 80 microgram/ml dose of protamine, both myocyte percent and velocity of shortening fell by greater than 50% when compared with isoproterenol alone values (p < 0.05). To determine the reversibility of these protamine effects, we performed additional experiments in the presence of heparin. Incubation with heparin before protamine addition prevented the negative effects of protamine on myocyte function. However, the addition of heparin after protamine incubation failed to reverse the negative effects of protamine on myocyte function. In a final set of experiments, the effects of protamine on isolated myocyte electrophysiologic properties were examined using microelectrode techniques at baseline and with either 40 or 80 micrograms/ml doses of protamine. Myocyte resting membrane potential changed from baseline with the addition of a 40 micrograms/ml dose of protamine (-79.2 +/- 0.5 versus -75.2 +/- 0.8 mV (p < 0.05), with no further change at an 80 micrograms/ml dose of protamine (-73.0 +/- 1.3 mV).(ABSTRACT TRUNCATED AT 400 WORDS)

Ventricular failure and cellular remodeling with chronic supraventricular tachycardia.

Chronic supraventricular tachycardia has been associated with ventricular dysfunction in human beings and in animals. The changes in ventricular size and shape and the myocyte remodeling that may occur with chronic supraventricular tachycardia are unknown. Left and right ventricular remodeling and myocyte changes were examined in 12 pigs after 3 weeks of atrial pacing (supraventricular tachycardia at 240 beats/min and in 10 control pigs (105 +/- 3 beats/min). Chronic supraventricular tachycardia resulted in decreased left ventricular and right ventricular ejection fractions compared with control values (left ventricle, 26% +/- 4% versus 60% +/- 1%; right ventricle, 19% +/- 3% versus 53% +/- 3%; p less than 0.05 for both), decreased wall thickness (left ventricle, 8.3 +/- 0.1 mm versus 10.5 +/- 0.2 mm; right ventricle, 2.8 +/- 0.3 mm versus 4.2 +/- 0.2 mm; p less than 0.05 for both), and increased end-diastolic volumes (left ventricle, 66 +/- 10 ml versus 54 +/- 4 ml; right ventricle, 78 +/- 8 ml versus 56 +/- 4 ml; p less than 0.05 for both). Myocardial water content was significantly higher with supraventricular tachycardia than in control pigs (left ventricle, 82% +/- 4% versus 76% +/- 4%; right ventricle, 83% +/- 4% versus 78% +/- 2%; p less than 0.05 for both). According to computer-aided stereological studies, the percent volume of myocytes in the subendocardial layer of the hearts that underwent supraventricular tachycardia was smaller than that of the control hearts (left ventricle, 62% +/- 2% versus 79% +/- 1%; right ventricle, 55% +/- 4% versus 77% +/- 1%; p less than 0.05 for both) and myocyte diameter was reduced (left ventricle, 16 +/- 1 microns versus 23 +/- 2 microns; right ventricle, 13 +/- 1 microns versus 22 +/- 2 microns; p less than 0.05 for both). Further, myocytes isolated from the left ventricles of the group with supraventricular tachycardia were significantly longer than were control myocytes (190 +/- 25 microns versus 145 +/- 30 microns, p less than 0.05 for both). In summary, chronic supraventricular tachycardia caused significant right and left ventricular failure, with a reduction in wall thickness and chamber dilatation. This was accompanied by a reduction in the percent volume of myocytes occupying the subendocardial layer, with reduced myocyte diameter and increased myocyte length and water content. These changes are likely to be important in understanding supraventricular tachycardia-induced ventricular dysfunction.

Wall thickness referenced to myocardial volume: a new noninvasive framework for cardiac mechanics.

Dimensional variables measured for study of left ventricular mechanics are subject to errors arising from difficulty in determining zero-stress dimensions for use as a reference. Based on a method validated for measurements within individuals, we have devised an approach that facilitates comparison between individuals while minimizing random scatter. We define an exact mathematical index of strain, ln(h(0)/h), using wall thickness (h) referenced to extrapolated wall thickness at zero-luminal volume (h(0)). Noninvasive data from rabbits, pigs, and humans all yielded highly similar myocardial stress, ln(h(0)/h), and work values. The stress-ln(h(0)/h) relationship during afterload variation was constant among individual pigs with a twofold variation in ventricular mass. Stress-ln(h(0)/h) data from our analysis displayed lower scatter than either pressure-volume data normalized to myocardial mass or stress-ln(h(0)/h) data referenced to end-diastolic dimensions. A Frank-Starling-like curve with high correlation (r(2) = 0.96) was constructed from single points from different pigs, suggesting a low level of size and intersubject scatter. This method offers high precision for noninvasive characterization of ventricular and myocardial mechanics and for comparisons between subjects and between species.

Cell and sarcomere contractile performance from the same cardiocyte using video microscopy.

The relationship between whole cell and sarcomere contractile performance from within the same myocyte remains unclear. In the present study, the dynamic properties of whole cell and sarcomere contractile performance were examined from the same myocyte by computer-assisted video microscopy. Isolated canine left ventricular myocytes were field stimulated at 1 Hz, and whole cell and sarcomere contractile performance was measured in the unloaded unattached state (n = 16) and after attachment to a basement membrane substrate (n = 18). Whole cell and sarcomere contractile measurements were obtained immediately on initiation of electrical stimulation as well as at steady state, after which measurements were repeated in the presence of 25 nM isoproterenol. Video-microscopic images of whole cell and sarcomere contractions were obtained at final magnifications of x1,100 and x5,500, respectively. By use of a 240-Hz high-scan-rate charge-coupled device camera and a video-based edge-detection system synchronized with the camera video output, the myocyte and sarcomere motion data were digitized. Steady-state percentage and velocity of shortening for whole cells and sarcomeres were 4.75 +/- 0.30% and 56.50 +/- 2.37 microns/s and 8.63 +/- 0.60% and 2.24 +/- 0.46 microns/s, respectively, for the attached myocytes and 8.63 +/- 0.48% and 71.38 +/- 6.14 microns/s and 11.73 +/- 3.22% and 2.72 +/- 0.62 microns/s, respectively, for the unattached myocytes. With the initiation of electrical stimulation, the extent of the shortening-velocity of relengthening relationship increased in a linear fashion for the attached (whole cell, r = 0.87; sarcomere, r = 0.90; both P < 0.001) and unattached myocytes (whole cell, r = 0.83; sarcomere, r = 0.88; both P < 0.001). In all experiments, isoproterenol significantly increased the slope of these linear relationships (P < 0.01). Furthermore, the relationship between whole cell and sarcomere velocity of shortening was highly linear (r > 0.91, P < 0.001). In summary, this study demonstrated that the video-based edge-detection technique could be adapted to measure cell and sarcomere contractile performance from the same myocyte. Furthermore, a significant linear relationship exists between whole cell and sarcomere contractile dynamics with alterations in both load and inotropic state.

Differential modulation of alpha 2-adrenergic and opioid spinal antinociception by cholecystokinin and cholecystokinin antagonists in the rat dorsal horn: an electrophysiological study.

Cholecystokinin (CCK) has been shown to reduce the spinal antinociceptive effects of opioid agonists such as morphine. The present study examined the effect of CCK and CCKB antagonists on the spinal antinociception mediated by the selective alpha 2-adrenergic agonist dexmedetomidine. Extracellular recordings of noxious-evoked C fibre responses of dorsal horn convergent neurones were made in the halothane-anaesthetized rat. Alone, intrathecal dexmedetomidine (5 micrograms) profoundly inhibited C fibre-evoked responses (92 +/- 7%). In the presence of 1 microgram intrathecal CCK the antinociceptive effect of dexmedetomidine was reduced to 27 +/- 11%. Inhibitions of C fibre-evoked responses mediated by submaximal doses (0.5 and 2.5 micrograms) dexmedetomidine were not altered by CCKB antagonists L365,260 (0.2 mg/kg subcutaneous) or PD135158 (10 micrograms intrathecal). Both CCKB antagonists did increase the inhibition of C fibre-evoked responses by the mu opioid agonists DAGOL and morphine. The results suggest CCK is able to inhibit spinal antinociception mediated via the activation of alpha 2-adrenergic receptors in addition to its well-documented interaction with spinal opioid analgesia. However the antagonist studies indicate an endogenous CCK control of spinal mu opioid mediated antinociception which does not extend to alpha 2-adrenergic antinociception.

Effects of procaine amide, quinidine and ethmozin on delayed afterdepolarizations.

We studied the effects of three chemically different antiarrhythmic drugs on ouabain-induced delayed afterdepolarizations (DAD) in canine Purkinje fibers. The three drugs, ethmozin, 4.6 X 10(-6) M; procaine amide, 1.1 X 10(-4) M; and quinidine, 1.13 X 10(-6) M reduced DAD amplitude equivalently at drive cycle lengths less than 500 ms. Quinidine and procaine amide in these concentrations had no effect on the action potential characteristics except for a prolongation of action potential duration (APD) induced by procaine amide. Ethmozin reduced action potential amplitude, maximum upstroke velocity of phase 0 (Vmax), and APD measured to 50% and full repolarization (APD50 and APD100). Rate dependent changes in Vmax and maximum diastolic potential (MDP) were not exaggerated by quinidine in the ouabain intoxicated Purkinje fibers. The DAD coupling interval was increased as DAD amplitude decreased with all three drugs. Although ethmozin, procaine amide and quinidine similarly reduced DAD amplitude; procaine amide and quinidine exerted these effects in the absence of other transmembrane potential effects, whereas ethmozin did so only in concentrations that depressed the action potential as well.

The developmental electrophysiologic effects of moricizine HCl on the canine cardiac Purkinje fiber.

Using standard microelectrode techniques, the developmental cellular electrophysiologic effects of moricizine HCl on adult and neonatal canine Purkinje fibers were studied. Steady state and rate-related changes in the transmembrane action potentials produced by moricizine HCl in both age groups were characterized and compared. Also, the rate of barium-induced abnormal automaticity before and after drug was also investigated in neonatal and adult Purkinje fibers. The major findings of this study are as follows. (1) The steady state and rate-related depressant effects of moricizine HCl on Vmax were similar in both age groups. (2) Moricizine HCl shortened APD90 in the adult fibers to a greater extent than in the neonate. (3) The concentration of moricizine HCl required to significantly reduce the rate of abnormal automaticity was less in the neonate than in the adult. The effect of moricizine HCl on APD90 of individual Purkinje fibers is influenced both by their control APD90 value as well as by maturational factors. It is less clear whether developmental differences in the effects of moricizine HCl on abnormal automaticity are solely a result of differences in control rates of abnormal automaticity between the two age groups.

A new framework for echocardiographic assessment of left ventricular mechanics: sensitivity to heart failure.

A recent report describes an approach to ventricular mechanics that employs mean end-systolic fiber stress and an exact mathematical strain index based on wall thickness referenced to myocardial mass. We used echocardiography and mean arterial pressures to determine the strain index and wall stress in (1) normal hearts from patients and swine, (2) swine with pacing-induced congestive heart failure, and (3) patients with dilated cardiomyopathy. Pigs were also studied under afterload variation with phenylephrine. Paired values of stress and strain index from control hearts (both swine and human) were tightly clustered. Values from animals and patients with congestive heart failure deviated from this cluster. Excellent separation (sensitivity 83%, specificity 94%) was displayed between control and paced pigs, despite confounding effects of varying afterload. We conclude that these variables display little change over a large range of normal cardiac mass, but deviate from this range during heart failure.

An infrared heat source for temperature control of a small microscope flow bath.

A simple, inexpensive, and easily installed infrared heat source with temperature controller for small superfusion baths used in electrophysiologic experiments is described. The output of a thermal sensor in the bath is amplified and sent to a feedback circuit which in turn controls the voltage supplied to a tungsten/halogen bulb focused on the bath. Fluctuation from the set point is no more than 0.2 degrees C with good fluid level control. Judging from the lack of change in the cardiac action potential duration, heart cells do not preferentially absorb infrared radiation.

Image-based display of activation patterns derived from scattered electrodes.

Presentation of electrophysiologic data, such as activation patterns, can take many forms, the most common of which are hand- or machine-drawn isochronal maps. We present an image-based method which provides accurate matching between electrophysiologic data and the anatomic sites from which the data were derived. This method is linear, simple, and straightforward to implement, and presents results in a format which is easy to understand and interpret.

Effect of mouth-rinse formulations on oral malodour processes in tongue-derived perfusion biofilm model.

An in vitro matrix biofilm perfusion model of tongue-derived microcosms for studying volatile sulfur compound (VSC) biogenesis has been previously described. The model was modified in order to monitor H(2)S in situ by use of a specialized electrode assembly based on microbial fuel cell technology. This system was designed to give real-time measurements expressed as electrode power output, which were proportional to H(2)S levels, measured by other means. In addition to the model modifications, the aim of this study was to demonstrate the biofilm responses following single or multiple exposure to biocidal, biostatic or VSC-inhibiting active compounds used in products. Tongue-derived biofilms (n = 6 per experiment) were perfused with one-fifth strength BHI at 20 ml h(-1) pH 7.2 and pulsed with putative treatment agent, placebo and controls including Zn(2+) ions and chlorhexidine (CHX). Compared with their pre-treatment conditions, all biofilms responded to the treatments in terms of reductions in hydrogen sulfide generation (as detected by the biofilm-electrode response) and other microbial volatile organic compounds (VOCs) as detected using a selected ion flow tube mass spectrometry analyser. The microbiological analysis of the treated and control biofilms show that test products (formulations with active agents) all gave reduced cell populations compared to the control biofilm. An order of effects (magnitude and duration) suggests that both the test agent and CHX produced the strongest reductions, distinct from the responses obtained for the placebo and water controls, which were largely similar. It is concluded that the in vitro perfusion model may be used to replicate many of the activities and reactions believed to be occurring by the tongue biofilm microflora within a real mouth, including H(2)S and VOC biogenesis and their inhibition by exposure to active agents.

Double-blind, placebo-controlled evaluation of extended-release bupropion in elderly patients with major depressive disorder.

Major depressive disorder in the elderly is associated with increased morbidity and reduced quality of life. This 10 week, placebo-controlled study investigated the efficacy and tolerability of extended-release bupropion (150-300 mg once daily) in depressed patients aged 65 years or older. The statistical assumptions necessary for the validity of the protocol-specified analysis of covariance were not met for the analysis of the primary outcome variable (Montgomery-Asberg Depression Rating Scale total score at Week 10, last observation carried forward). Alternative statistical methods used for the analysis of this variable demonstrated statistical significance. Statistically significant improvements were observed on the majority of secondary end points when compared with placebo, including the health outcome measures for motivation and energy, and life satisfaction and contentment. Adverse events were generally mild to moderate and similar between treatment groups. This study demonstrated that the extended-release bupropion is an effective, well-tolerated treatment for major depression in the elderly.