A multicenter study of primary graft failure after infant heart transplantation: impact of extracorporeal membrane oxygenation on outcomes.

Primary graft failure is the major cause of mortality in infant HTx. The aim of this study was to characterize the indication and outcomes of infants requiring ECMO support due to primary graft failure after HTx. We performed a retrospective review of all infants (<1 yr) who underwent Htx from three institutions. From 1999 to 2008, 92 infants (<1 yr) received Htx. Sixteen children (17%) required ECMO after Htx due to low cardiac output syndrome. Eleven (69%) infants were successfully weaned off ECMO, and 9 (56%) infants were discharged with a mean follow-up of 2.3 ± 2.5 yr. Mean duration of ECMO in survivors was 5.4 days (2-7 days) compared with eight days (2-10 days) in non-survivors (p = NS). The five-yr survival rate for all patients was 75%; however, the five-yr survival rate was 40% in the ECMO cohort vs. 80% in the non-ECMO cohort (p = 0.0001). Graft function within one month post-Htx was similar and normal between ECMO and non-ECMO groups (shortening fraction = 42 ± 3 vs. 40 ± 2, p = NS). For infants, ECMO support for primary graft failure had a lower short-term and long-term survival rate vs. non-ECMO patients. Duration of ECMO did not adversely impact graft function and is an acceptable therapy for infants after HTx for low cardiac output syndrome.

Methamphetamine-induced rapid and reversible changes in dopamine transporter function: an in vitro model.

This laboratory has demonstrated that a single methamphetamine (METH) injection rapidly and reversibly decreases the activity of the dopamine transporter (DAT), as assessed ex vivo in synaptosomes prepared from treated rats. This decrease does not occur because of residual drug introduced by the original injection or nor is it associated with a change in binding of the DAT ligand WIN35428. The purpose of this study was to elucidate the mechanism or mechanisms of this METH effect by determining whether direct application of this stimulant to synaptosomes causes changes in DAT similar to those observed ex vivo. Similar to the ex vivo effect, incubation of striatal synaptosomes with METH decreased DAT activity, but not WIN35428 binding: the effect on activity was not eliminated by repeated washing of synaptosomes. Also, as observed ex vivo, incubation with 3,4-methylenedioxymethamphetamine, but not cocaine or methylphenidate, caused a METH-like reduction in DAT function. The rapid and reversible METH-induced diminution in DAT activity did not occur because of a change in membrane potential, as assessed in vitro and ex vivo by [(3)H]tetraphenylphosphonium accumulation. However, the METH-related decline in DAT function may be attributed to phosphorylation because NPC15437, a protein kinase C inhibitor, attenuated the METH-induced decline in DAT function. Similarities between previously reported effects ex vivo of a single METH injection on serotonin and norepinephrine transporter function and effects of direct METH application in vitro were also found. Together, these data demonstrate that the in vitro incubation model mimics the rapid and reversible effects observed after a single METH injection.

Adrenocorticotropic hormone fragment ACTH/MSH(4-10 can act as a discriminative stimulus in rats.

Five of eight male albino rats learned to discriminate the effects of ACTH/MSH(4-10) (100 micrograms/kg, SC) from those of saline vehicle in a food-reinforced T-maze task. Generalization tests showed that the ACTH/MSH(4-10) cue was dose related with an ED50 of approximately 68.0 micrograms/kg. These findings indicate that ACTH/MSH(4-10) has interoceptive stimulus properties discriminable to some animals, which might provide a useful model for studying the pharmacology of this neuroactive peptide. Moreover, since ACTH/MSH(4-10) induces effects similar to those of ACTH/MSH in the central nervous system but not hormonally, these data suggest that endogenous ACTH or MSH may also have interoceptive stimulus effects unrelated to peripheral endocrine activity.

Differential effects of psychostimulants and related agents on dopaminergic and serotonergic transporter function.

High-dose administrations of amphetamine, methamphetamine, cathinone, methcathinone or methylenedioxymethamphetamine rapidly decrease dopamine and serotonin transporter function in vivo, as assessed in striatal synaptosomes obtained from drug-treated rats. In contrast, high-dose injections of fenfluramine, cocaine or methylphenidate had little or no effect on the activity of these transporters. Interestingly, the capacity of these agents to directly alter dopamine and serotonin uptake, as assessed in vitro by direct application to rat striatal synaptosomes, did not predict their potential to modulate transporter activity following in vivo administration. These findings demonstrate heretofore-unreported differences in the effects of these agents on monoamine transporter function, and a distinction between drug effects after direct application in vitro vs. administration in vivo.

Involvement of dopamine uptake in the discriminative stimulus effects of cocaine.

The involvement of dopaminergic and adrenergic mechanisms in the stimulus effects of cocaine was studied in rats trained to discriminate cocaine from saline. The cocaine (10mg/kg) cue generalized to compounds that act primarily by inhibiting DA uptake with an order of potency of nomifensine (ED(50) = 0.38mg/kg) > GBR12909 (1-{2-[bis(4-fluorophenyl) methoxy]-ethyl]}-4(3-phenylpropyl) piperazine (ED(50) = 4.38mg/kg) > bupropion (ED(50) = 11.6mg/kg) but not to those that: (1) directly activate postsynaptic DA receptors (bromocriptine), (2) release DA (amantadine), (3) have antagonist actions at presynaptic DA receptors (cis-flupenthixol) or, (4) inhibit the uptake of NE (desipramine, imipramine, nisoxetine). When given in combination with cocaine, the D2 receptors antagonist (-)sulpiride had no significant effects on cocaine-lever selection. These results suggest that inhibition of DA uptake is involved in the discriminative stimulus properties of cocaine since, (1) compounds that act by inhibiting DA uptake rather than through some other mechanism mimic cocaine and, (2) the reported affinities of these drugs for the DA transport site and their order of potency in blocking cocaine are identical.

The role of monoamine uptake in the discriminative stimulus effects of cocaine and related compounds.

The involvement of monoamine neurotransmitter uptake in the discriminative stimulus effects of cocaine was examined in rats (n = 48) trained to discriminate 10mg/kg of this substance from saline in a two-level, water-reinforced (FR 20), drug discrimination situation. Compounds that act primarily by inhibiting dopamine (DA) uptake substituted for the cocaine cue; the order of potency was mazindol > nomifensine > GBR 12909 > bupropion, although efficacy was lowest with GBR 12909. Desipramine, which inhibits norepinephrine (NE) uptake, substituted partially for cocaine while two drugs that inhibit serotonin (5-HT) uptake, citalopram and fluoxetine, did not mimic cocaine. When given in combination with cocaine, cis flupenthixol and SCH 23390 reduced responding on the cocaine-appropriate lever significantly and to a greater extent than either haloperidol, (+/-) sulpiride or (-) sulpiride; neither (+) sulpiride nor metergoline had significant effects. Cocaine substitutions with DA uptake inhibitors were also attenuated to varying extents by cis-flupenthixol, SCH 23390 and haloperidol, but not by metergoline. These data, in conjunction with results reported previously, suggest that inhibition of DA uptake is involved to a greater extent than either NE or 5-HT uptake in the discriminative stimulus properties of cocaine and related compounds. Since both the cocaine cue and its substitution by DA uptake inhibitors appear to be blocked most effectively, reliably and potently by compounds that act either non-selectively at DA receptors (cis-flupenthixol) or primarily at D1 receptors (SCH 23390), D1 mechanisms may play a particularly important role in the neuronal substrates of these behavioral effects.

Sustained compression and healing of chronic venous ulcers.

STUDY OBJECTIVE: Comparison of four layer bandage system with traditional adhesive plaster bandaging in terms of (a) compression achieved and (b) healing of venous ulcers. DESIGN: Part of larger randomised trial of five different dressings. SETTING: Outpatient venous ulcer clinic in university hospital. PATIENTS: (a) Pressure exerted by both bandage systems was measured in the same 20 patients. (b) Healing with the four layer bandage was assessed in 148 legs in 126 consecutive patients (mean age 71 (SE 2); range 30-96) with chronic venous ulcers that had resisted treatment with traditional bandaging for a mean of 27.2 (SE 8) months. INTERVENTIONS: (a) Four layer bandage system or traditional adhesive plaster bandaging for pressure studies; (b) four layer bandaging applied weekly for studies of healing. END POINTS: (a) Comparison of pressures achieved at the ankle for up to one week; (b) complete healing within 12 weeks. MEASUREMENTS AND MAIN RESULTS: (a) Four layer bandage produced higher initial pressures at the ankle of 42.5 (SE 1) mm Hg compared with 29.8 (1.8) for the adhesive plaster (p less than 0.001; 95% confidence interval 18.5 to 6.9). Pressure was maintained for one week with the four layer bandage but fell to 10.4 (3.5) mm Hg at 24 hours with adhesive plaster bandaging. (b) After weekly bandaging with the four layer bandage 110 of 48 venous ulcers had healed completely within 12 (mean 6.3 (0.4)) weeks. CONCLUSION: Sustained compression of over 40 mm Hg achieved with a multilayer bandage results in rapid healing of chronic venous ulcers that have failed to heal in many months of compression at lower pressures with more conventional bandages.

Nitric oxide in the evaluation of congenital heart disease with pulmonary hypertension: factors related to nitric oxide response.

Inhaled nitric oxide (NO) has been used in the preoperative evaluation of patients with congenital heart disease and pulmonary hypertension. The purpose of this study was to characterize responses in pulmonary vascular resistance (PVR) to oxygen and increasing doses of NO during cardiac catheterization and to determine if any related factors affect the response of the pulmonary vascular bed to NO. A prospective analysis of 42 patients (median age, 3.0 years) with congenital heart disease and pulmonary hypertension who underwent NO testing was performed. Systemic vascular resistance (SVR) and PVR were assessed in room air, 100% oxygen, and oxygen plus 20, 40, and 80 parts per million (ppm) NO. Changes in pulmonary artery pressure, PVR, and SVR were assessed. The response to NO was then correlated to individual patient's age, gender, type of heart defect, the presence of trisomy 21, and baseline PVR/SVR. There was a greater decrease in PVR and PVR/SVR with 20 ppm NO than with oxygen alone. There was no additional decrease at 40 or 80 ppm NO. There was no correlation between age, gender, type of congenital heart disease, and baseline PVR/SVR ratio with the degree of response to NO. Patients with trisomy 21 had less of a response to NO (p = 0.017) than patients without trisomy 21. There is no difference in determining PVR response with doses of NO beyond 20 ppm during cardiac catheterization. Age, gender, and baseline PVR/SVR ratio are not associated with responsiveness to NO. Patients with trisomy 21 may be less responsive to NO.

Behavioral treatment of obesity. Limitations and results with the chronically obese.

Results of behavioral treatment for obese persons during the first 18 months of clinical operation are presented and other reports in the literature are reviewed. Baseline and follow-up data were gathered from a population of 144 female, chronically obese patients, most of whom were experiencing medical complications associated with obesity. Treatment results were disappointing in comparison with results of similar programs. Difference in patient population groups is offered as a possible explanation for this phenomenon. Covariant analyses of demographic and psychosocial variables failed to yield any clear predictors of weight loss; it is suggested that biological factors may be important to treatment outcome for some overweight patients.

Update on the management of obesity.

This article updates a paper published in this journal more than a decade ago. We detail the ensuing decade's developments in the treatment of obesity, reviewing innovations, established techniques, and the current status of behavior modification. We evaluate newer developments, such as anorectic drugs, very low calorie diets, and intragastric balloon bezoars, and we describe other approaches to the treatment of obesity, such as residential and comprehensive outpatient programs. We conclude by recommending a multidisciplinary approach to this complex problem.