Treatment recommendations for the use of antipsychotics for aggressive youth (TRAAY). Part I: a review

OBJECTIVES: To review the evidence for the safety and efficacy of nonpharmacological and pharmacological treatments for aggression in children and adolescents. METHOD: and searches (1990-present) were conducted for double-blind, placebo-controlled studies of atypical antipsychotics for aggression and for literature on the use of other pharmacological agents and psychosocial interventions for aggression. Case reports and adult literature regarding the safety of atypical antipsychotics were used where controlled data for youth were lacking. RESULTS: Controlled data on the treatment of aggression in youth is scarce. Psychosocial interventions may be effective alone or in combination with pharmacological treatments. Psychotropic agents (e.g., stimulants, mood stabilizers, beta-blockers) have also been shown to have limited efficacy in reducing aggression. Antipsychotics, particularly the atypical antipsychotics, show substantial efficacy in the treatment of aggression in selected pediatric populations. Atypical antipsychotics are generally associated with fewer extrapyramidal symptoms than are typical antipsychotics. CONCLUSIONS: Psychosocial interventions and atypical antipsychotics are promising treatments for aggression in youth. Double-blind studies should examine the safety and efficacy of atypical antipsychotics compared to each other and to medications from other classes, the efficacy of specific medications for different subtypes of aggression, combining various psychotropic medications, optimal dosages, and long-term safety.     

Obesity resistance and enhanced glucose metabolism in mice transplanted with white adipose tissue lacking acyl CoA:diacylglycerol acyltransferase 1

Recent studies have identified the white adipose tissue (WAT) as an important endocrine organ that regulates energy and glucose metabolism via a number of secreted factors. Mice lacking acyl CoA:diacylglycerol acyltransferase 1 (DGAT1), a key enzyme in mammalian triglyceride synthesis, are protected against diet-induced obesity and glucose intolerance because of increased energy expenditure and enhanced insulin sensitivity. Because DGAT1 is highly expressed in WAT, we hypothesized that DGAT1 deficiency affects the expression of adipocyte-derived factors that regulate energy and glucose metabolism. Here we show that the transplantation of DGAT1-deficient WAT decreases adiposity and enhances glucose disposal in wild-type mice. Analysis of DGAT1-deficient WAT revealed a twofold increase in the expression of adiponectin, a molecule that enhances fatty acid oxidation and insulin sensitivity, and this increase may account in part for the transplantation-induced metabolic changes. Our results highlight the importance of the endocrine function of WAT and suggest that an alteration in this function contributes to the increased energy expenditure and insulin sensitivity in DGAT1-deficient mice.     

A one year health economic model comparing transdermal fentanyl with sustained-release morphine in the treatment of chronic noncancer pain

A Markov model was constructed to simulate the resource use and health outcomes of one year of treatment comparing the fentanyl transdermal therapeutic system (fentanyl-TTS) with oral sustained-release (SR) morphine in outpatients with noncancer pain in Denmark. Effectiveness was assessed in terms of days of good pain control and days on initial treatment. Costs included those of baseline pain management, including breakthrough pain; co-medication costs; and control of adverse events. Fentanyl-TTS was more effective than SR-morphine in achieving good pain control (99 vs. 64 days, respectively) and the incremental cost-effectiveness of fentanyl-TTS was US dollars 10.26 per extra day of good pain control. Patients treated with fentanyl-TTS remained considerably longer on initial treatment compared with those treated with SR-morphine (166 days vs. 117 days, respectively). The results of this study suggest that fentanyl-TTS is a competitive therapeutic and economic choice for the treatment of chronic noncancer pain.     

Selective Expression of β Tubulin Isotypes in Gerbil Vestibular Sensory Epithelia and Neurons

The seven mammalian isotypes of tubulin are strikingly similar in amino acid sequence. The differences in isotypic sequence, although small, are nonetheless conserved in evolution, which suggests that they may confer distinct functional roles. If so, such roles should be reflected in the selective expression of isotypes by cell type, or even in the sorting of isotypes to within-cell pools. Hair cells of the vestibular sensory epithelia each possess a kinocilium, a microtubule-based organelle that could represent a distinct microtubule compartment, separate from the extensive microtubule network in the soma. The afferent neurons that innervate the vestibular sensory epithelia may also be functionally divided into dendritic, somatic, and axonal compartments, each with its own complement of microtubules. We have examined the distribution of tubulin isotypes in gerbil vestibular epithelia using isotype-specific antibodies to four isotypes and indirect immunofluorescence. We found that hair cells selectively express _I and _IV tubulin, while supporting cells express _I, _II, and _IV tubulin. However, no sorting of isotypes between somatic and kinocilia compartments was found in hair cells. Vestibular ganglion cells display three isotypes in the soma, axon, and terminal dendrite compartments (_I, _II, and _III tubulin), but only _III tubulin was found in calyceal nerve endings. The implication of these findings is that tubulin isotypes are not sorted to within-cell compartments in hair cells but are sorted in some vestibular neurons.     

Diffusing capacity: how to get it right

The carbon monoxide diffusing capacity test (D(LCO)) is a commonly performed pulmonary function test that requires technical expertise and attention to detail to get acceptable results. With the advent of automated devices and powerful computer programs, D(LCO) measurement has rapidly gained wide clinical acceptance. But there are many subtle aspects to performing the test that can diminish its accuracy and repeatability. The clinician must ensure: that the D(LCO) instrument is correctly calibrated; that inhalation is least 90% of the largest previously measured vital capacity; that the patient executes a quick, smooth inhalation within 2 seconds; that the breath-hold is 9-11 seconds; that the breath-hold is without straining (no Valsalva or Müller maneuvers); that exhalation is quick and smooth; that a representative gas sample is obtained from the correct portion of the exhalation; and that at least 5 minutes elapse between D(LCO) tests. At least 2 but no more than 5 D(LCO) tests should be conducted, and testing is complete when 2 tests are within 10% or 3 D(LCO) units (mL CO/min/mm Hg) of each other. The reported D(LCO) value is the average of the first 2 tests that meet the reproducibility criteria, but if 5 tests are performed and no 2 meet the reproducibility criteria, the reported value is the average of the 2 tests with the highest inspiratory volumes. These quality controls will help laboratories achieve consistent high D(LCO) accuracy.     

Importance of amino acids of the central portion of the second intracellular loop of the gastrin-releasing Peptide receptor for phospholipase C activation,internalization, and chronic down-regulation

Little is known about the function of the central portion of the second intracellular loop (i2 loop) of peptide receptors in activation of downstream pathways and receptor modulatory processes such as receptor internalization or chronic down-regulation (DR). Recent data suggest a role for i2 loop hydrophobic amino acids in these processes. We used site-directed mutagenesis to address these issues with the gastrin-releasing peptide receptor (GRP-R). Each i2 loop residue from 142 to 148 was mutated and the receptors were expressed in Balb 3T3 cells. Two mutants showed a minimal (<2-fold) decrease in affinity. Five mutants showed decreased efficacy for activating phospholipase C (PLC). Two double mutants (IM143.147AA and VM144.147AA) showed a minimal decrease in affinity but had a decreased ability to fully activate PLC. Only the IM double mutation had decreased maximal internalization, whereas the R145A single mutant showed an increase, suggesting a tonic inhibitory role for Arg-145 in internalization. Three single and both double mutants showed decreases in receptor DR. There was a weak correlation between the extent of GRP-R internalization and the maximal PLC activation, whereas changes in the maximal PLC activation were significantly (p = 0.008) coupled to receptor DR. This study shows that amino acids of the i2 loop of the GRP-R are important in activation of PLC, internalization and down-regulation, but not for affinity. Our results support the proposal that internalization and chronic down-regulation have differing dependence on PLC and are largely independent processes, because some mutants showed no changes in internalization, but significant alterations in down-regulation.     

Ventilation performance of a mixed group of operators using a new rescue breathing device-the glossopalatinal tube

INTRODUCTION: We studied how effectively a mixed group of helpers could ventilate a manikin with a new rescue breathing device after a short period of instruction. The device consists of a mouthcap, a "glossopalatinal tube" (GPT) reaching between tongue and palate and a connector for a bag, ventilator or the rescuers mouth. Rather than reaching behind the tongue like an oropharyngeal airway (OP), it is able to scoop the tongue off the posterior pharyngeal wall when tilted by the rescuer. It was compared with a conventional face mask with an OP. METHODS: The study made use of an anaesthesia simulator (MedSim Ltd., Israel) and a manikin. 46 subjects with different professional backgrounds (anaesthesia nurses, medical students, emergency medical technicians (EMTs), physicians training for anaesthesiology) underwent a standard introduction to the GPT and OP (lecture with demonstration on an intubation trainer, illustrated brochure). They ventilated the manikin for 5 min each using the bag plus GPT and the OP plus face mask, respectively, in random order after the simulator had been made apnoeic and the simulated arterial oxygen saturation (S(aO(2))) had dropped to 80%. The actions and the results (tidal volumes (V(t)), S(aO(2))) were recorded on video. The subjects graded difficulty of operation and fatigue on a visual analogue scale (VAS). RESULTS AND CONCLUSIONS: Mean V(t) with the OP plus mask amounted to 463 (230-688 ml), with GPT to 426 (243-610 ml) (median [10-90% percentiles]) (P=0.047). No differences were observed with respect to the time a S(aO(2))> or =90% was maintained (OP plus mask: 255 (139-266 s), GPT: 255 (90-269 s)) or the grades for fatigue (OP plus mask: 58% of VAS, GPT: 48% of VAS, median) and difficulty (OP plus mask: 16% of VAS, GPT: 21% of VAS). Performance and grades were scattered over a wide range. Success with the two devices was correlated, but the subjects judgement tended to diverge. The GPT is an easy to learn alternative to conventional devices and might be helpful in clinical emergencies, including situations of unexpectedly difficult ventilation.     

Differential recruitment of endogenous pain inhibitory systems in neuropathic pain patients

Neuronal hyperexcitability is a key finding in patients with neuropathic pain. Contributing to hyperexcitability may be decreased activity in the endogenous pain inhibitory systems. The present study aimed at recruiting descending inhibition, by the use of painful heterotopic stimulation (HTS), in 16 patients with peripheral chronic neuropathic pain and associated brush-evoked allodynia. Two experiments were performed: one examined the effect of HTS on ongoing pain and intensity of brush-evoked allodynia and the other tested the effect of HTS on ongoing pain and area of brush-evoked allodynia. Both experiments consisted of two sessions, one with painful cold HTS (1 degrees C water bath) another with non-painful neutral HTS (32 degrees C water bath). The area of brush-evoked allodynia was significantly reduced (P=0.003) during painful HTS, as compared to non-painful HTS. In contrast, neither the intensity of brush-evoked allodynia nor the ongoing pain was significantly changed. The results indicate that endogenous pain modulating systems can alter some aspects of chronic neuropathic brush-evoked allodynia. The differential effect of painful HTS on ongoing pain and area of brush-evoked allodynia suggest that separate mechanisms are involved.     

Physical performance tests for people with spinal pain--sensitivity to change

Objective : The sensitivity to change for six physical performance tests for assessing impairments and activity limitations in persons with spinal pain was examined.

Method : Eighty men and 106 women with long-term spinal pain participating in a randomized controlled study went through the tests on inclusion in the study, and were then invited to follow-up tests after 5 weeks and 6 months. The tests were a 'step-on-stool test', three gait tests and two lifting tests (PILE tests). Sensitivity to change was examined by relating changes in physical performance to self-rated concepts assumed to reflect a real change in the individual. Effect sizes were calculated.

Results : Sensitivity to change in absolute values was revealed for the gait test with burden, the stair-climbing test and the PILE cervical test for women. Only the PILE cervical test showed responsiveness to clinically important change according to our criteria. Moderate to high effect sizes were found for all tests. Relatively few subjects improved to an extent considered clinically important. Improvement was greater in subjects whom inclusion measurements showed to be less fit.

Conclusions : The sensitivity to change was moderate over a 6-month period for the physical performance tests. The gait test with burden, the stair-climbing test and the PILE tests were most sensitive to change. It is suggested that these tests be incorporated in an 'assessment instrument bank' for physiotherapists, supplemented with other reliable and valid tests relevant to the problems for the individual with spinal pain.