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Overlapping sequential pulses. A new waveform for transthoracic defibrillation.

BACKGROUND: A directionally changing shock electrical vector could facilitate defibrillation by depolarizing myocytes with different orientations vis-à-vis the shock field. Such a changing vector can be achieved by a new waveform for transthoracic defibrillation: overlapping sequential pulses. Our purpose was to evaluate this waveform. METHODS AND RESULTS: Ventricular fibrillation was induced in closed-chest dogs. Single and overlapping truncated exponential waveform pulse shocks were then administered from self-adhesive chest electrodes. Single pulse (control) shocks were 7.5-millisecond duration, while the sequential overlapping pulse shocks, using two different pathways, consisted of two pulses, each 5.0-millisecond duration; the second pulse began 2.5 milliseconds after the start of the first pulse and ended 2.5 milliseconds after the end of the first pulse. Thus, the total duration of the sequential overlapping shock was 7.5 milliseconds. During the overlap phase (2.5 milliseconds), the electrical vector orientation is the summation of the individual vectors. Two different electrode placements and corresponding electrical vector orientations were studied: group 1 (n = 14), left lower chest to right upper chest (pulse 1), overlapped by right lower chest to left upper chest (pulse 2), with the sequence then reversed; and group 2 (n = 11), left chest to right chest (pulse 1) overlapped by dorsal (vertebral column) to ventral (sternum) (pulse 2) with the sequence then reversed. At voltages equivalent to energies of 50, 100, and 150 J, the sequential overlapping pulse shocks achieve higher success rates than the single pulse shocks: At the low energy, 50 J, single pulse shock success rates were 0% (group 2) and 14% (group 1), while the overlapping pulse shocks achieved success rates of 39% (group 2) and 55% (group 1) (P < .05). Similarly, at the highest energy tested, 150 J, single pulse shock success rates were 45% (group 2) and 61% (group 1), while the overlapping pulse shock success was 91% (group 2) and 95% (group 1) (P < .05). In a third group of dogs (n = 3), intracardiac plunge electrodes placed orthogonally in the septum showed that the orthogonal components of intracardiac voltage gradient change varied markedly during the three phases of the sequential overlapping shocks, demonstrating the changing direction of the net electrical vector as the shock proceeded. In a fourth group of dogs (n = 5), short-duration (2.5-millisecond) single pulse shocks were compared with longer 7.5-millisecond single pulse shocks and with the sequential overlapping pulse shocks, all at equivalent energies. Despite substantially higher current flow, the 2.5-millisecond-duration single pulse shocks were not more effective than 7.5-millisecond single pulse shocks, and both 2.5- and 7.5-millisecond duration single pulse shocks had markedly inferior success rates compared with the sequential overlapping pulse shocks. CONCLUSIONS: Sequential overlapping pulse shock waveforms facilitate defibrillation compared with single pulse shocks of the same total energy. This is due at least in part to the changing orientation of the electrical vector during the multiple pulse shock.

Animals↗

The significance of small pulses of gonadotrophin-releasing hormone.

A series of experiments was conducted to ascertain the significance of 'small' pulses of gonadotrophin-releasing hormone (GnRH). In the first experiment, ovariectomized hypothalamo-pituitary disconnected (HPD) ewes were given 250 ng pulses of GnRH every 2 h for 1 week, 25 ng pulses every 2 h for 24 h, 25 ng pulses hourly for 24 h and then alternating hourly pulses of 25 and 250 ng. During the 25 ng pulses, LH was not detectable in plasma and FSH concentrations declined after 2 days. Following the 25 ng pulses, the resumption of 250 ng pulses led to exaggerated LH responses (mean +/- S.E.M. pulse amplitude 18.7 +/- 1.7 vs 10.2 +/- 1.2 micrograms/l in the first week). In a second experiment, ovariectomized-HPD ewes were maintained on 250 ng GnRH pulses every 2 h for 1 week and were then given three 25 ng pulses mid-way between the 250 ng pulses. Samples of blood were taken over three 250 ng pulses without 25 ng insertions and over three pulses with insertions. The insertion of 25 ng GnRH pulses did not cause LH pulses in their own right and did not alter the LH responses to the 250 ng pulses. In a third experiment, 50 ng GnRH pulses were inserted between the 250 ng GnRH pulses, as in experiment 2; these 50 ng pulses caused small LH pulses and led to a reduction in the response of the LH pulse amplitude to the 250 ng pulses. The 'small' LH pulses which occurred in response to 50 ng GnRH compensated for the reduced responses to the 250 ng pulses.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Short biphasic pulses from 90 microfarad capacitors lower defibrillation threshold.

For defibrillation between right ventricular and retropectoral patch electrodes using truncated exponential pulses, the stored energy defibrillation threshold (DFT) is lower for short pulses from small 60-microF capacitors than for conventional pulses from 120-microF capacitors, but 60-microF pulses frequently require higher voltages than are currently used. The goal of this study was to determine if DFT could be reduced by intermediate size 90-microF capacitors. This study compared biphasic waveform DFTs for 120 microF-65% tilt pulses, 90 microF-65% tilt pulses, and 90 microF-50% tilt pulses in 20 patients at defibrillator implantation. The 90 microF-50% tilt pulses were selected because their duration is half that of 120 microF-65% tilt pulses. The stored energy DFT for 90 microF-50% tilt pulses (9.1 +/- 4.3 J) was less than both the DFT for 120 microF-65% tilt pulses (12.0 +/- 5.5 J, P < 0.005) and the DFT for 90 microF-65% tilt pulses (11.6 +/- 5.8 J, P < 0.005). There was no significant difference between the latter two values. The voltage DFTs for 90 microF-50% pulses (436 +/- 113 V) and 120 microF-65% tilt pulses (436 +/- 104 V) were not statistically different; the voltage DFT for 90 microF-65% tilt pulses was higher than for either of the other two pulses (490 +/- 131, P < 0.005). The DFT was 20 J or greater in three patients for both 120 microF-65% tilt pulses and 90 microF-65% tilt pulses, but it was 16 J or less in all patients for 90 microF-50% tilt pulses. When pathways were dichotomized by the median resistance of 71 omega, 90 microF-50% tilt pulses significantly reduced DFTs compared to 120 microF-65% tilt pulses for higher resistance pathways (9.2 +/- 4.0 J vs 13.0 +/- 6.2 J, P = 0.002), but not lower resistance pathways (9.0 +/- 4.8 J vs 10.9 +/- 4.6 J, P = NS). For the electrode configuration tested, biphasic 90 microF-50% tilt pulses reduce stored energy DFT in comparison with 120 microF-65% tilt pulses without increasing voltage DFT. However, 90 microF-65% tilt pulses provide no benefit.

Defibrillators, Implantable↗

Catheter-mediated electrical ablation: the relation between current and pulse width on voltage breakdown and shock-wave generation.

Voltage waveform breakdown is characteristic of barotraumatic shock-wave generation during electrical catheter ablation of cardiac arrhythmias. The purpose of this investigation was to avoid barotrauma by defining, in vitro, the limits of pulse amplitude and pulse width for rectangular constant-current pulses that do not result in voltage breakdown and subsequently to determine what pulsing frequency is safe for use when high-energy trains of pulses are used. Electric pulses were delivered with a variable waveform modulator with a wide dynamic range and bandwidth capable of delivering pulses of 30-10,000-mu sec duration with amplitudes of up to 25 A. Cathodal pulses were delivered to a 6F catheter immersed in fresh anticoagulated bovine blood warmed to 37 degrees C to stimulate the milieu of a catheter in the chambers of the human heart. The maximum pulse amplitude that could be delivered without incurring voltage waveform breakdown varied inversely with pulse duration. Pulses of 30 mu sec broke down at currents above 24 A (2,500 V). Pulses of 10,000-mu sec duration broke down at 1 A (250 V). The maximum safely delivered energy for a single pulse was 2.5 J for pulses of 80-120 mu sec. Peak power for single pulses was maximum at 50-55 kW with 30-50-mu sec pulses. Charge delivery for single pulses was maximized at 9 mC with long, 10,000-mu sec duration pulses. To deliver an electrical pulse with energy significantly greater than 2.5 J without incurring voltage breakdown, trains of pulses were delivered where each pulse in the train had previously been shown to be free of voltage breakdown.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Treatment of tinea capitis with itraconazole capsule pulse therapy.

BACKGROUND: The number of newly diagnosed cases of tinea capitis in children appears to be on the rise, particularly in urban centers. OBJECTIVE: The purpose of this study was to assess the effectiveness, safety, and compliance of itraconazole pulse therapy for tinea capitis. METHODS: Fifty subjects (48 children [less than 18 years of age] and 2 adults) with tinea capitis were treated with pulse itraconazole in a multicenter evaluation. Each pulse lasted 1 week, with 2 weeks between the first two pulses and 3 weeks between the second and third pulses. The decision to administer a second or third pulse was determined by the response of the subject at the time that the next pulse was due. During the 1-week pulse of active therapy, itraconazole (5 mg/kg/day) was dosed as follows: more than 40 kg, 200 mg per day (two capsules per day); 20 to 40 kg, 100 mg per day (one capsule per day); and 10 to 19 kg, 50 mg per day (one half of a capsule per day). The duration of the study was 12 weeks with mycologic evaluation at this time. Subjects who were classified as treatment failures at 12 weeks after the start of therapy were given the option of receiving an additional 1-week pulse of active therapy, with 3 weeks between successive pulses. RESULTS: The causative organisms were Trichophyton tonsurans (41 subjects), T violaceum (7), T. soudanense (1), and T rubrum (1). Thirteen subjects were lost to follow-up, with 37 subjects (35 children and 2 adults) available for evaluation 12 weeks after the start of therapy. At this time, cure (clinical and mycologic) was observed in 30 (81%) of 37 subjects. When the tinea capitis was mild, cure was obtained after one pulse in two subjects and after two pulses in five subjects. With tinea capitis of moderate extent, complete cure was obtained after one pulse in one subject, two pulses in eight subjects, and after three pulses in seven subjects. When tinea capitis was severe, two and three pulses produced complete cure in one and six subjects, respectively. Of the seven subjects whose conditions failed to respond (three subjects with moderate disease and four subjects with severe disease), five subjects chose to receive extra itraconazole. Clinical and mycologic cure was observed after four pulses in four subjects and after five pulses in one subject. There were no associated clinical adverse effects with itraconazole therapy. CONCLUSION: With tinea capitis, itraconazole pulse therapy is effective and safe and is associated with high compliance. The pulse regimen enables the duration of treatment to be individualized, according to the extent of disease and its rate of resolution.

Antifungal Agents↗

Effects of gonadotropin-releasing hormone pulse frequency modulation on the reproductive axis of photoinhibited male Siberian hamsters.

In Siberian hamsters, photostimulation evokes differential release of the gonadotropins, with FSH rising rapidly and LH levels rising much later. We have tested the hypothesis that differential release of gonadotropins in this species can be mediated by changes in the frequency of pulsatile GnRH stimulation. Photoinhibited Siberian hamsters received GnRH pulses at frequencies of 1 pulse every 45 (fast), 90 (medium), or 180 min (slow). Animals were killed at 0, 3, 5, 10, 20, and 30 days after treatment. There was a clear GnRH pulse frequency effect on LH release, with fast pulses > medium pulses > slow pulses > short-day (SD) controls. In addition, 10 days of fast-frequency GnRH pulses produced LH levels significantly greater than LH levels in animals exposed to 10 days of medium or slow GnRH pulse frequencies. Pulsatile GnRH produced the following serum FSH relationships: medium pulses > fast pulses > SD. The FSH response to slow GnRH frequency fell between the two faster frequencies. The effect of GnRH pulse frequency on paired testes weight was as follows: fast pulses = medium pulses > slow pulses > SD controls. The differing GnRH pulse frequencies produced the following testosterone relationships; fast pulses > medium pulses = slow pulses = SD controls. These results agree with studies showing that slower GnRH pulse frequencies facilitate FSH release, while faster GnRH pulse frequencies favor LH release. Our observations are also consistent with the idea that the singular release of FSH after transfer of hamsters to a long-day photoperiod is mediated by alterations in the frequency of endogenous pulsatile GnRH release.

Animals↗

Effects of pulse separation on detection thresholds for electrical stimulation of the human cochlea.

Effects of pulse separation on detection of electrical stimulation of the cochlea were studied in 12 profoundly deaf human subjects with Nucleus 22 cochlear implants. Biphasic symmetric pulses were used. Pulse separation is the time from offset of one biphasic pulse to the onset of the next biphasic pulse in the train. Effects of pulse separation were studied in the context of different covariables in four stages of the experiment. Effects of pulse separation seen in the different stages were similar, despite the different covariables. Both pulse separation and the total number of pulses per stimulus seem to be important variables affecting stimulus detection. For 0.5 ms/phase pulses, thresholds were lowest at the shortest pulse separations tested (0.2-1.1 ms) and increased as a function of pulse separation. For 2 ms/phase pulses, detection thresholds were lowest at pulse separations around 7.5 ms, in most cases, and higher at both longer and shorter pulse separations. These results suggest that interactions among adjacent pulses can either hinder or facilitate detection of the signal depending on the magnitudes of pulse separation and phase duration. Pulse separations at which thresholds measured for 2 ms/phase pulses were minimum were fairly consistent across subjects and did not correlate well with speech recognition scores. However, significant variation in this measure across species has been seen.

Adult↗

Decrements in per pulse release of norepinephrine, antagonist potentiation of release and presynaptic receptor theory.

In recent decades the theory that amine transmitter release at nerve terminals is routinely regulated through negative feedback systems sensing and responding to the instantaneous perineuronal concentration of previously liberated transmitter has assumed pre-eminence. However, observations indicate a major drop off in per pulse transmitter release when only two or four stimulation pulses are administered, reflecting the unexpectedly prompt operation of feedback inhibition. We explored this quandary in our understanding of control of transmitter release by axonal depolarization versus terminal feedback using isotopic norepinephrine and in vitro slices of rabbit hippocampus. A technique of continuous collection of superfusate over a 30min cycle of stimulation utilizing a wide range of intervals between individual stimulation pulses was used. Following simulation with single pulses even 60s apart or pseudo one pulses 150s apart a marked decline in per pulse release was noted. The deficits in per pulse release were not related to the number of pulse delivered at any time over the course of a 30min stimulation period. The pulse decrements were independent of the activity of neuronal uptake and of superfusion flow rate or even individual pulse duration and frequency. Presynaptic receptor antagonists, potentiated efflux near maximally with the second of only two pulses. Potentiations were independent of pulse number, pulse duration, or frequency. No linkage between perineuronal transmitter concentrations and the antagonist potentiation of release was found. However, the decrements in per pulse release with multiple pulses and the potentiation by alpha presynaptic antagonists occurred under the same test conditions. We conclude that the pulse deficit can be looked at as largely attributable to an enhanced efflux with delivery of the first pulse in a train of pulses, rather then to a pattern of progressively declining efflux linked to increasing extracellular transmitter levels as frequency and pulse number increase.

Adrenergic alpha-Antagonists↗

A physiological role for sporadic interruptions of the dopaminergic tone in the genesis of big mass prolactin pulses.

The present studies were designed to evaluate pulsatile PRL secretion after the establishment of either a continuous dopaminergic input or a complete blockade of the dopaminergic inhibitory tone. Adult female rats on estrus and male rats implanted with indwelling jugular cannulae were bled at 3-min intervals for a 3-h period. Bromocriptine (CB-154) and domperidone (DOM) were administered sc and iv, respectively. The administration protocol used for both treatments produced either a continuous dopaminergic input (CB-154 treatment) or a complete dopaminergic blockade (DOM treatment). Pulse analysis was performed on the data series using the algorithm Detect. In both estrous female and male rats, dopaminergic receptor activation by CB-154 reduced peak and trough values, pulse amplitude, area under the pulse, and mean PRL levels. In contrast, a complete dopamine (DA) receptor blockade by DOM increased these parameters. Domperidone treatment increased pulse frequency and reduced pulse interval and duration. Bromocriptine, however, differentially affected some pulsatility parameters depending on the sex of the rats. In females, CB-154 did not alter any of the qualitative parameters (frequency, pulse interval, and duration) of pulsatile PRL secretion. In contrast, in male rats the treatment reduced frequency and duration while increasing pulse interval. CB-154 reduced basal PRL levels in male rats, whereas in estrous females this parameter was not altered. PRL pulses were further evaluated by frequency distribution analysis, using the area under the pulses divided by the baseline to normalize the data due to treatment-induced differences in baselines. This calculation allows the estimation of the amount of hormone released per pulse over the baseline. In both estrous female and male rats, two classes of PRL pulses were identified. One class corresponded to pulses containing a small mass of hormone [small mass pulses (SM)], while the others were characterized by pulses containing a large mass of hormone [big mass pulses (BM)]. Interestingly, both the dopaminergic agonist CB-154 and the dopaminergic antagonist DOM dramatically diminished BM pulse incidence in both estrous female and male rats. In fact, BM pulses were practically absent in both experimental groups. To further substantiate this notion, animals of each experimental group were assigned to one of the following categories: animals depicting BM and SM pulses or rats presenting solely SM pulses.(ABSTRACT TRUNCATED AT 400 WORDS)

Activity Cycles↗

Universal equations for linear adiabatic pulses and characterization of partial adiabaticity.

A numerical analysis of the sech/tanh (or hyperbolic secant) and tanh/tan adiabatic inversion pulses provides a set of master equations for each type of pulse that guarantee their optimal implementation over a wide range of practical conditions without needing to further simulate the inversion profiles of the pulses. These simple equations determine the necessary maximum RF amplitude (RF(max)) required for a preselected degree of inversion across a chosen effective bandwidth (bw(eff)) and for a chosen pulse length (T(p)). The two types of pulse function differently: The sech/tanh pulse provides a rectangular inversion profile with bw(eff) being a large fraction of the adiabatic frequency sweep (bwdth), whereas for tanh/tan bw(eff) is < or =bwdth/20. If the quality of inversion is defined as the minimum allowable extent of inversion, iota(bw), at the boundaries of bw(eff), two basic linear equations are found for both types of pulse and these are of the form (RF(max)T(p))(2)=m(1)T(p)bwdth+c(1) and T(p)bwdth=m(3)T(p)bw(eff)+c(3). The different behavior of the two pulses is expressed as different dependencies of the slopes m(n) and intercepts c(n) on iota(bw) and allowances are made for second order effects within these equations. The availability of these master relationships enables a direct comparison of the two types of adiabatic pulse and it is found that tanh/tan requires about half the pulse length of an equivalent sech/tanh pulse and also has the advantage of being less sensitive to the effects of scalar coupling. In contrast sech/tanh delivers about half the total RF power of an equivalent tanh/tan pulse. It is expected that the forms of these two basic linear equations are generally applicable to adiabatic inversion pulses and thus define the concept of "linear adiabaticity." At low values of T(p)bwdth or T(p)bw(eff) the linear equations no longer apply, defining a region of "partial adiabaticity." Normal adiabatic pulses in the middle of this partial region are more efficient in terms of RF(max) or T(p) but are moderately less tolerant to RF inhomogeneity. A class of numerically optimized pulses has recently been developed that specifically trades adiabaticity in an attempt to gain RF(max) or T(p) efficiency. In comparison to normal adiabatic pulses implemented under optimal conditions, these new partially adiabatic pulses show only marginal improvements; they are restricted to single values of T(p)bw(eff), and they are vastly less tolerant to RF inhomogeneity. These comparisons, and direct comparisons between any types of inversion pulse, adiabatic or otherwise, can be made using plots of (RF(max)T(p))(2) or (Total Power) T(p) versus T(p)bw(eff).

Magnetic Resonance Spectroscopy↗

Pituitary responsiveness to diurnal and nocturnal GnRH pulses in melatonin-treated ewe lambs.

It has been shown that oral administration of melatonin to Suffolk ewe lambs, from 10 weeks of age onwards, advances the onset of puberty compared with control lambs maintained under the same natural photoperiod. Luteinizing hormone (LH) pulse frequency at 20 and 26 weeks of age was unchanged by melatonin. However, LH pulse amplitudes greater than 1 ng mL(-1) were consistently observed in melatonin-treated lambs, suggesting either a high responsiveness of the pituitary gland to endogenous gonadotrophin-releasing hormone (GnRH) pulses, or a large amount of GnRH released by each pulse. The purpose of the present study was to assess the pituitary responsiveness to six diurnal and six nocturnal exogenous pulses of GnRH (10 ng kg(-1) bodyweight) in melatonin-treated ewe lambs (3 mg melatonin daily at 1600 hours, from 10 weeks of age; n = 5) and control lambs of the same age (n = 5), born in the spring and kept under natural photoperiod. Pulses of GnRH were given intravenously at 60-min intervals by means of an indwelling jugular catheter from 0900 to 1400 hours and from 2100 to 0200 hours to ewe lambs of 20 and 26 weeks of age. Blood samples were collected at 10-min intervals using a contralateral jugular vein catheter from 1 h before and up to 1 h after the last GnRH pulse. The difference (delta) between plasma LH concentrations at 0 min and the greatest concentration of LH after each GnRH pulse was calculated and compared in the same group. The total area under the GnRH response curve (AUC) was also calculated and compared within and between the groups. The AUC of melatonin-treated lambs (66.1 +/- 5.94 and 52.24 +/- 7.42 ng mL(-1)/6 h, diurnal and nocturnal respectively) was greater than that of control lambs (39.42 +/- 4.29 and 32.82 +/- 3.6 ng mL(-1)/6 h diurnal and nocturnal respectively; P<0.05) at 20 weeks of age. At 26 weeks of age, only the diurnal total AUC was greater in melatonin-treated lambs than in control lambs (60.17 +/- 7.98 and 29.8 +/- 5.02 ng mL(-1)/6 h respectively; P<0.05). Delta LH concentrations in response to the first diurnal pulse of GnRH were greater than those in response to the fifth diurnal GnRH pulse (P<0.05) in melatonin-treated lambs of 20 weeks of age. Also, the delta LH concentrations in response to the first three diurnal GnRH pulses were greater than to the last three nocturnal pulses of GnRH (P<0.05). Delta LH concentrations were greater in response to the second diurnal pulse of GnRH than to the last three diurnal GnRH pulses, and greater than the responses to the first and the last four nocturnal GnRH pulses (P<0.05), at 26 weeks of age in melatonin-treated lambs. The response to nocturnal pulses of GnRH was similar. In control lambs, the responses to diurnal and nocturnal GnRH pulses were similar at 20 and 26 weeks of age. These results suggest that melatonin enhances the pituitary responsiveness to GnRH pulses in ewe lambs.

Aging↗

Differential actions of thyrotropin (TSH)-releasing hormone pulses in the expression of prolactin and TSH subunit messenger ribonucleic acid in rat pituitary cells in vitro.

The influence of TRH pulse pattern on PRL and TSH alpha- and beta-subunit gene expression was examined in vitro. Pituitaries from adult female rats were dissociated and plated for 48 h to allow attachment to collagen-coated microcarrier beads. The beads were perifused for 24 h with TRH (pulses or continuous). To examine the effects of TRH pulse amplitude, TRH pulses (0.032-100 nM) were given every 60 min (controls received either medium pulses or continuous 100 nM TRH). PRL mRNA rose progressively to a peak at 4 nM TRH/pulse (93% increase vs. medium-pulsed controls), but higher TRH pulse amplitudes were less effective. alpha-Subunit mRNA also rose with increasing TRH pulse dose, with maximal (137%) elevations after 100-nM pulses. TSH beta mRNA concentrations were increased by TRH pulse doses between 0.8-20 nM, but a clear dose-response pattern was not seen. Continuous TRH (100 nM) resulted in PRL, TSH beta, and alpha mRNAs that were less than the values in medium-pulsed controls. To assess the effects of pulse frequency, 4-nM TRH pulses were given at intervals between 15-240 min (controls received medium pulses or continuous 4 nM TRH). PRL mRNA was increased (55-107% increase) after all pulse intervals, except 240 min, and rose to a similar degree after 4 nM TRH given continuously. alpha-Subunit mRNA concentrations increased by a lesser degree and also did not rise after the slowest (240 min) pulse interval. In contrast, TSH beta mRNA levels increased progressively as pulse intervals were increased, and maximal (85%) elevations were seen after 240-min pulses. Continuous 4 nM TRH did not alter alpha or TSH beta mRNAs. These results show that pulsatile TRH is more effective than continuous TRH in stimulating PRL, TSH beta, and alpha mRNAs. Further, the pattern of TRH pulsatile signals can influence the expression of these pituitary hormone genes in a differential manner.

Animals↗

Generation of human lymphokine-activated killer cells following an IL-2 pulse in elderly cancer patients.

The toxicity of high-dose interleukin 2 (IL-2) treatments limits its use in tumour therapies, particularly in older age groups, characterized by a reduced tolerance to antineoplastic therapies. Here, we evaluated the possibility to induce cytotoxic lymphokine-activated killer (LAK) cells through a brief exposure (1-h pulse) of peripheral blood mononuclear cells (PBMC) from elderly cancer patients to high concentrations of IL-2. The cytotoxic activity, phenotype, apoptosis, and cell cycle phase of IL-2 pulsed PBMC were determined and compared with those of non-pulsed PBMC cultured continuously in IL-2. Significant levels of LAK cytotoxicity were obtained in pulsed PBMC from all patients examined. The mean values of lytic activity on day 6 of culture were lower, even if not significantly, in pulsed than non-pulsed cultures. The pulsed cells were phenotypically similar to non-pulsed lymphocytes with regards to the expression of CD3, CD4, CD8, CD16, and CD56 antigens. The induction of activation markers, like CD25 and CD122 IL-2 receptors and CD71 transferrin receptor, was also comparable in pulsed and non-pulsed cultures. When a lower cytotoxicity was found in pulsed cultures, a lower number of CD54+ (ICAM-1) cells was also found. LAK cell cytotoxicity and number of CD54 cells were significantly correlated. No difference was found between pulsed and non-pulsed cultures in their cell cycle phase or in the percentage of apoptotic cells. Autologous plasma did not inhibit the differentiation of pulsed PBMC into LAK cells. The IL-2 pulse of PBMC from healthy young donors resulted in the induction of LAK cytotoxicity as observed in elderly cancer patients. The results demonstrate the effectiveness of IL-2 pulse to generate cytotoxic LAK cells in elderly cancer patients suggesting the potential application of pulsing procedures to treatment of older age groups.

Adult↗

Different pulse shapes to obtain small fiber selective activation by anodal blocking--a simulation study.

The aim of this study was to investigate whether it is possible to reduce a charge per pulse, which is needed for selective nerve stimulation. Simulation is performed using a two-part simulation model: a volume conductor model to calculate the electrical potential distribution inside a tripolar cuff electrode and a human fiber model to simulate the fiber response to simulation. Selective stimulation is obtained by anodal block. To obtain anodal block of large fibers, long square pulses (> 350 micros) with a relatively high currents (1-2.5 mA) are usually required. These pulses might not be safe for a long-term application because of a high charge per pulse. In this study, several pulse shapes are proposed that have less charge per pulse compared with the conventional square pulse and would therefore be safer in a chronic application. Compared with the conventional square pulse, it was possible to reduce the charge with all proposed pulse shapes, but the best results are obtained with a combination of a square depolarizing pulse and a blocking pulse. The charge per pulse was up to 32% less with that pulse shape than with a square pulse. Using a hyperpolarizing anodal prepulse preceding a square pulse, it was not possible to block nerve fibers in a whole nerve bundle and to obtain reduction of a charge per phase. Reduction of the charge could be achieved only with spatially selective blocking. The charge per phase was larger for the combination of a hyperpolarizing anodal prepulse and a two-step pulse than for the two-step pulse alone.

Action Potentials↗

A comparative study of a 595-nm with a 585-nm pulsed dye laser in refractory port wine stains.

BACKGROUND: The pulsed dye laser (PDL) is the treatment of choice for port wine stains (PWS); however, some patients' PWS become refractory to further treatments. Technological advances have enabled new machines with the advent of surface cooling devices to deliver longer wavelengths and higher fluence more safely. These advances have the potential to achieve improved response rates in refractory PWS. There are few studies comparing the efficacy of standard PDL treatments for refractory PWS with the wider choice of treatment variables available from newer PDL machines. OBJECTIVES: To determine if there is any advantage of using a longer wavelength (595 nm) and pulse widths (1.5 ms, 6 ms and 20 ms) over conventional PDL settings (wavelength 585 nm, pulse width 1.5 ms) in refractory PWS. METHODS: Eighteen consecutive consenting patients with Fitzpatrick skin types 1-4 with a mean age 35 years (range 17-59 years) with refractory PWS were treated routinely with three separate test areas using 595-nm PDL (using three different pulse width settings of 1.5 ms, 6 ms and 20 ms), compared with test areas treated with 585-nm PDL (pulse width 1.5 ms). All test areas were treated with an identical fluence (15 J cm(-2)), spot size (7 mm) and cooling setting (dynamic cooling 60 ms, delay 60 ms). RESULTS: We found a statistically significant advantage of 595-nm PDL (pulse width 1.5 ms) over 595-nm PDL (pulse width 6 ms) (P < 0.05) in the treatment of refractory PWS; however, we found no significant advantage using longer pulse widths of 20 ms compared with 1.5 ms with the 595-nm PDL. There was no statistically significant advantage in using a 595-nm PDL over a 585-nm PDL using identical pulse widths of 1.5 ms, spot size, fluence and cryogen cooling settings; however, the number of directly comparable test areas was smaller. Some individual patients in our study obtained a better response with certain 595-nm PDL settings (pulse width 1.5 ms and 6 ms) compared with 585-nm PDL (pulse width 1.5 ms). CONCLUSIONS: Our experience of high fluence PDL in the treatment of refractory PWS suggests patients treated with 585 nm (pulse width 1.5 ms) improve to a similar degree as patients treated with 595-nm PDL (pulse width 1.5 ms). However, the use of the 595-nm PDL with longer pulse widths yields no extra advantage. For those patients who have failed to improve with high-fluence 585-nm PDL (pulse width 1.5 ms), test areas using 595-nm PDL (pulse width 1.5 ms and 6 ms) should be undertaken to ascertain if individual patients may benefit from the longer pulse width 595-nm PDL.

Adolescent↗