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Effect of total spinal anesthesia on arterial and venous responses to dopamine and dobutamine.

To test whether acute denervation alters the vascular effects of dopamine and dobutamine, we anesthetized 16 greyhounds and placed them on total cardiopulmonary bypass (CPB). Eight dogs received total spinal anesthesia before drug testing; eight dogs were tested in the absence of total spinal anesthesia. During dopamine and dobutamine infusions, venous capacitance [determined by the volume of the CPB venous reservoir (VR)] and mean arterial pressure (MAP) were monitored. The CPB pump flows remained constant throughout our studies. Every dog received six increasing doses of both drugs. In the absence of total spinal anesthesia, both dopamine and dobutamine increased VR (decreased venous capacitance) in a dose-dependent manner. Dobutamine decreased MAP in a dose-related fashion but dopamine had no significant effect on MAP. After total spinal anesthesia, both dopamine and dobutamine produced greater dose-related increases in VR (i.e., decreases in venous capacitance) than in the absence of spinal anesthesia. Dopamine increased MAP but dobutamine had no significant effect. These data demonstrate how dopamine and dobutamine differ in their effects on the arterial circulation in the presence or absence of spinal anesthesia. The acute denervation of spinal anesthesia altered venous and arterial dose-response relationships of both drugs. Finally, our study demonstrates the effectiveness of dobutamine and, perhaps even more so, dopamine as possible alternatives to ephedrine for the pharmacologic correction of the noncardiac circulatory sequelae of spinal anesthesia.

Anesthesia, Spinal↗

Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine.

Accumulating evidence suggests that microglial cells in the spinal cord play an important role in the development of neuropathic pain. However, it remains largely unknown how glia interact with neurons in the spinal cord after peripheral nerve injury. Recent studies suggest that the chemokine fractalkine may mediate neural/microglial interaction via its sole receptor CX3CR1. We have examined how fractalkine activates microglia in a neuropathic pain condition produced by spinal nerve ligation (SNL). SNL induced an upregulation of CX3CR1 in spinal microglia that began on day 1, peaked on day 3, and maintained on day 10. Intrathecal injection of a neutralizing antibody against CX3CR1 suppressed not only mechanical allodynia but also the activation of p38 MAPK in spinal microglia following SNL. Conversely, intrathecal infusion of fractalkine produced a marked p38 activation and mechanical allodynia. SNL also induced a dramatic reduction of the membrane-bound fractalkine in the dorsal root ganglion, suggesting a cleavage and release of this chemokine after nerve injury. Finally, application of fractalkine to spinal slices did not produce acute facilitation of excitatory synaptic transmission in lamina II dorsal horn neurons, arguing against a direct action of fractalkine on spinal neurons. Collectively, our data suggest that (a) fractalkine cleavage (release) after nerve injury may play an important role in neural-glial interaction, and (b) microglial CX3CR1/p38 MAPK pathway is critical for the development of neuropathic pain.

Analysis of Variance↗

Intrathecal baclofen. Effects on nocturnal leg muscle spasticity.

Electromyographic activity was recorded from tibialis anterior during nocturnal polysomnography in six patients with severe spasticity of spinal origin. The patients had a baclofen reservoir system implanted subcutaneously into their lumbar subarachnoid space and were studied for two nights in a double-blind, placebo controlled, crossover design. Tibialis anterior electromyographic activity per hour of sleep was reduced on the night of baclofen infusion. In particular, less electromyographic activity occurred after arousal from sleep.

Adult↗

Effects of intrathecal methotrexate and cytosine arabinoside on the radiation tolerance of the rat spinal cord.

The effect of intrathecally or intravenously administered methotrexate (MTX) or cytosine arabinoside (ara-C) on the early and late delayed radiation response of the rat cervical spinal cord has been studied. A technique has been developed for intrathecal administration of drugs into the rat lumbar spinal canal. When given shortly before irradiation, intrathecal ara-C significantly reduces the isoeffect doses for the early delayed white matter necrosis syndrome by a factor of 1.2-1.3, while no effect is observed for the late delayed vascular syndrome. The effect disappears when ara-C is given intravenously or 24 h after irradiation. In addition, intrathecal ara-C seems to impair the capacity of long-term regeneration. Intrathecal administration of MTX is limited by severe acute neurotoxicity. At a maximally tolerated intrathecal MTX dose, no modification of the early or late radiation response of the spinal cord was observed. In contrast to ara-C, intravenous MTX seems to interact with the induction of the late delayed vascular damage in the rat cervical spinal cord, with a dose-modifying factor of 1.1-1.2.

Animals↗

Serotonergic modulation of cat bladder function before and after spinal transection.

Micturition was evoked in conscious cats by infusing saline into the bladder at a physiological rate. Drugs were administered intrathecally. Micturition volume threshold was increased by 5-hydroxytryptamine (5-HT, serotonin) and decreased by zatosetron, a 5-HT3 receptor antagonist, in spinally intact cats. Thus 5-HT3 receptors inhibit micturition. After complete spinal transection, serotonin reduced volume threshold in 3 of 4 cats, indicating an alteration in serotonergic control. However, 2-methyl-5-HT, a 5-HT3 receptor agonist, increased volume threshold. Thus 5-HT3 receptor-mediated inhibition of bladder function remains after spinal transection. We conclude that some, but not all, serotonergic modulation of bladder function is altered after spinal transection.

Animals↗

The contribution of remifentanil to middle latency auditory evoked potentials during induction of propofol anesthesia.

There is a debate regarding whether opioids, as a component of general anesthesia, are adequately reflected in the assessment of anesthesia based on derivatives of the electroencephalogram. To test the hypothesis of a possible quantitative contribution of remifentanil on middle latency auditory evoked potentials, we studied its interaction with propofol anesthesia in 45 unpremedicated male patients undergoing elective lower limb orthopedic surgery. They were allocated randomly to three groups. The first two groups received remifentanil either with a high (8 ng mL(-1)) or a low (3 ng mL(-1) target concentration using target-controlled infusion (TCI). The third group received spinal anesthesia instead of remifentanil. Anesthesia was induced by a stepwise increase in propofol concentration using TCI. The auditory evoked potential index (AEPex) and calculated propofol effect site concentrations were determined at loss of consciousness and the reaction to laryngeal mask airway insertion was noted. The propofol infusion was then converted to a closed-loop TCI using an AEPex value of 40 as the target. We found no significant contribution of remifentanil alone on the auditory evoked response, whereas increasing concentrations of remifentanil led to a significant decrease of the calculated propofol effect site concentrations (P = 0.023) necessary for unconsciousness. Prediction probability for AEPex was inversely related to the remifentanil concentration and was best for the control group, which received propofol alone. These results support previous findings of a quantitative interaction between remifentanil and propofol for loss of consciousness but question the specific contribution of remifentanil to auditory evoked potentials.

Adult↗

Insulin decreases isoflurane minimum alveolar anesthetic concentration in rats independently of an effect on the spinal cord.

UNLABELLED: The observation that insulin supplies an element of analgesia suggests that insulin administration might decrease the concentration of inhaled anesthetic required to produce MAC (the minimum alveolar anesthetic concentration required to eliminate movement in response to noxious stimulation in 50% of subjects). We hypothesized that insulin decreases MAC by directly affecting the nervous system, by decreasing blood glucose, or both. To test these hypotheses, we infused increasing doses of insulin either intrathecally or IV in rats anesthetized with isoflurane and determined the resulting MAC change (assessing forelimb and hindlimb movement separately). Infusion of insulin produced a dose-related decrease in MAC that did not differ among groups. That is, the IV and intrathecal infusions caused similar decreases in MAC at a given infusion rate. Blood glucose concentrations were larger in the rats given insulin with 5% dextrose. However, the percentage change in MAC determined from forelimb versus hindlimb movement did not differ. For a given insulin infusion rate, MAC changes and glucose levels did not correlate with each other, except, possibly, for the most rapid infusion rate, for which smaller glucose concentrations were associated with a marginally larger decrease in MAC. Intrathecal infusions of insulin did not produce spinal cord injury. In summary, we found that insulin decreases isoflurane MAC in a dose-related manner independently of its effects on the blood concentration of glucose. The sites at which insulin acts to decrease MAC appear to be supraspinal rather than spinal. The effect may be due to a capacity of insulin to produce analgesia through an action on one or more neurotransmitter receptors. IMPLICATIONS: Intrathecal and IV insulin administration equally decrease isoflurane MAC in rats, regardless of the concentration of blood sugar. These findings indicate that although insulin decreases MAC, the decrease is not mediated by actions on the spinal cord.

Anesthetics, Inhalation↗

Intrathecal infusion of bupivacaine with or without morphine for postoperative analgesia after hip and knee arthroplasty.

Postoperative pain after major orthopaedic operations can be controlled by continuous intrathecal administration of opioids or local anaesthetics. Effective intrathecal analgesia can be achieved through synergism of low doses of the two analgesic drugs and, possibly, less drug-related adverse effects. Therefore, we have evaluated the usefulness of a combined low-dose bupivacaine and morphine infusion in patients undergoing hip and knee arthroplasty. Spinal anaesthesia was induced in 55 ASA I-III patients with 0.5% bupivacaine 2 ml via a 28-gauge spinal catheter (L3-4 interspace) and 0.5-ml increments were given if needed. Intrathecal 24-h infusions consisted of bupivacaine 2 mg h-1 alone (n = 18), bupivacaine 1 mg h-1 alone (n = 18) or bupivacaine 1 mg h-1 combined with morphine 8 micrograms h-1 (n = 19). The interview after 3, 6, 12 and 24 h included assessment of pain at rest and on movement (VAS scale), occurrence of sensory and motor block and nausea/vomiting. Bupivacaine 1 mg h-1 combined with an infusion of morphine provided as good postoperative analgesia as bupivacaine 2 mg h-1, but motor block disappeared earlier (P = 0.01). Patients in the bupivacaine 1-mg h-1 group required more supplementary doses of oxycodone i.m. than the other groups (P = 0.04). Time to first oxycodone dose from the start of intrathecal infusion did not differ between groups. The frequency of nausea and vomiting was similar in all groups. In spite of this, antiemetic medication was required more often in the bupivacaine 1-mg h-1 group (possible because of opioid rescue medication). On the ward, one patient in the bupivacaine 2-mg h-1 group experienced a new increase in sensory block with concomitant hypotension. One patient in the same group had minor decubitus on the heel of the operated leg, probably because of prolonged motor block. We conclude that intrathecal infusion of a combination of bupivacaine 1 mg h-1 and morphine 8 micrograms h-1 produced adequate postoperative analgesia. Unfortunately, postoperative nausea and vomiting was a frequent disturbing adverse effect.

Adult↗

Local infusion of nerve growth factor attenuates myelinated nerve fiber sprouting into lamina II of the spinal dorsal horn and reduces the increased responsiveness to mechanical stimuli in rats with chronic constriction nerve injury.

PURPOSE: To clarify the relationship between allodynia and the sprouting of myelinated fibers, we examined whether the administration of nerve growth factor (NGF) affected the paw withdrawal response to non-noxious mechanical stimuli and the sprouting of myelinated fibers into lamina II of the spinal dorsal horn, using a chronic constriction injury model of the sciatic nerve. METHODS: Mechanical allodynia was determined as the threshold of the withdrawal response stimulated by von Frey filaments. Sprouting was examined using horseradish peroxidase conjugated to the B fragment of cholera toxin (B-HRP). NGF was continuously infused into the site of nerve injury for 14 days after nerve ligation. RESULTS: With vehicle infusion, significantly increased responsiveness to mechanical stimuli was observed on postoperative days (PODs) 5, 7, and 14 after ligation, compared with before surgery, and B-HRP-positive fibers were newly localized in lamina II on PODs 7 and 14. Infusion of NGF reduced the responsiveness to mechanical stimuli on 5, 7, and 14 PODs and B-HRP-positive fibers in lamina II on PODs 7 and 14. CONCLUSION: We propose that the suppression of the increased responsiveness to mechanical stimuli produced by NGF could be related to the disappearance of B-HRP-positive fibers in lamina II.

Journal Article↗

Baclofen in the treatment of cerebral palsy.

Baclofen, a gamma-aminobutyric acid agonist, acts at the spinal cord level to impede the release of excitatory neurotransmitters that cause spasticity. Oral baclofen improves cerebral spasticity mildly, but its activity is limited because of its poor lipid solubility. Cerebrospinal fluid baclofen levels after intrathecal administration are many times higher than those achieved after oral administration. Continuous intrathecal baclofen infusion has been used to treat cerebral spasticity in two patient groups: in older ambulatory children with inadequate underlying leg strength, and in patients with severe spasticity in both the upper and lower extremities. Responsiveness to intrathecal baclofen is confirmed by test injections before insertion of a programmable subcutaneous pump. Continuous intrathecal baclofen infusion dosages vary from 27 to 800 micrograms/day. Continuous intrathecal baclofen infusion reduces spasticity in the upper and lower extremities, and improves upper extremity function and activities of daily living but has no effect on athetosis in the dosages used to treat spasticity. Complications related to the intrathecal catheter occur in approximately 20% of patients, and infection requiring pump removal occurs in approximately 5%. Preliminary studies indicate that continuous intrathecal baclofen infusion alleviates some forms of generalized dystonia associated with cerebral palsy.

Administration, Oral↗

Activity-dependent development of cortical axon terminations in the spinal cord and brain stem.

Corticospinal (CS) axon terminations in several species are widespread early in development but are subsequently refined into a spatially more restricted distribution. We studied the role of neural activity in sensorimotor cortex in shaping postnatal development of CS terminations in cats. We continuously infused muscimol unilaterally into sensorimotor cortex to silence neurons during the postnatal CS refinement period (weeks 3-7). Using anterograde transport of WGA-HRP, we examined the laterality of terminations from the muscimol-infused (i.e., silenced) and active sides in the spinal cord, as well as in the cuneate nucleus and red nucleus. We found that CS terminations from the muscimol-infused cortex were very sparse and limited to the contralateral side, while those from the active cortex maintained an immature bilateral topography. Controls (saline infusion, noninfusion) had dense, predominantly contralateral, CS terminations. There was a substantial decrease in the spinal gray matter area occupied by terminations from the side receiving the blockade and a concomitant increase in the area occupied by ipsilateral terminations from the active cortex. Optical density measurements of HRP reaction product from the active cortex in muscimol-infused animals showed substantial increases over controls in the ratio of ipsilateral to contralateral CS terminations for all laminae examined (IV-V, VI, VII). Our findings suggest that ipsilateral dorsal horn terminations reflect new axon growth during the refinement period because they are not present there earlier in development. Those in the ventral horn are present earlier in development and thus could reflect maintenance of transient terminations. Increased ipsilateral terminations from active cortex were due to recrossing of CS axons in lamina X and not to an increase in labeled CS axons in the ipsilateral white matter. Examination of brain stem terminations suggested that, between postnatal weeks 3 and 7, development of corticocuneate terminations also is activity-dependent but that development of corticorubral terminations is not. Activity-dependent CS development is a plausible mechanism by which early motor experiences could shape the anatomical and functional organization of the motor systems during a critical postnatal period.

Aging↗

Reduced sodium output following acute spinal injury.

STUDY DESIGN: Assessment of sodium output in spinal injury patients. OBJECTIVES: The purpose was to examine the effects of sodium loading acutely by an infusion, long term by sodium supplements, to acutely injured spinal patients on a fixed sodium intake. This was compared with another group of acutely injured patients who were on a hospital diet of between 50 and 150 mmol of sodium daily. SETTING: The National Spinal Injuries Centre, Stoke Mandeville Hospital, Aylesbury, Bucks HP21 8AL, UK. METHODS: A total of 53 studies were carried out on 52 patients between 1962 and 1964. In all, 49 patients were studied during the first 10 days after injury as follows: a control group of 39 patients received no supplementary sodium, two received NaCl infusion, two NaCl tablets orally, and six received NaCl infusion followed by NaCl tablets orally. Four patients were studied for more than 15 days after injury (one of these had been studied in the acute stage); they received NaCl infusion and one (42d) received in addition NaCl tablets for four subsequent days. RESULTS: In all patients urinary sodium excretion was minimal on day 2 and increased thereafter. On days 2-6, it was significantly lower in patients with a complete transection of the cervical cord than in patients with lower lesions. In the early studies, nine patients excreted less than 40% of the administered load within 24 h. In four of these patients excretion was 10% or less. In the later studies, three of the four patients excreted at least 80% of the infused Na+ on the same day. CONCLUSION: Sodium retention in the patient with cord injury is a response to trauma. The different responses seen in patients with different levels of cord transection are not due to direct changes in the innervation of the kidney but to compensation for sympathetic insufficiency, blood pressure being maintained by the secretion of aldosterone, vasopressin and other hormones. The decreased urinary output seen acutely after cord transection is not due to renal failure and the patient's condition can be made dangerously worse by attempts to create a diuresis.

Administration, Oral↗

[Intrathecal administration of morphine, midazolam, and their combination in 4 patients with chronic pain].

We have evaluated the analgesic effect of continuous intrathecal administration of midazolam in 4 patients using a three-level score (no change, amelioration, and marked improvement). The secondary effects of this drug were also investigated (sedation, nausea, vomiting, respiratory depression, urinary retention, motor dysfunction). In one patient midazolam was the only drug administered, whereas in three patients this drug was associated with morphine. In one patient with a peripheral arteriopathy, midazolam at a dose of 12 mg/day was unable to equal the analgesic effect achieved with 0.4 mg of morphine. The remaining three patients had carcinoma and received a continuous intrathecal perfusion of morphine at increasing daily doses up to 12; 4,8; and 6 mg/day, respectively without pain relief. In these patients the association of midazolam at respective doses of 9; 4-8; and 6 mg/day induced amelioration in one patient and marked improvement in the two other patients. Midazolam did not change the heart rate, respiratory rate, arterial blood pressure, nor body temperature. We believe that the analgesic effect of intrathecal administration of midazolam is due to its coupling with the ionophore complex GABA-spinal benzodiazepine that in turn produces an increment of the GABA amino butyric acid at this level.

Adenocarcinoma↗

Spinal or systemic analgesia after extensive spinal surgery: comparison between intrathecal morphine and intravenous fentanyl plus clonidine.

STUDY OBJECTIVE: To compare two different methods of postoperative analgesia after extensive spinal fusion. DESIGN: Double-blind, randomized study. SETTING: University-affiliated hospital. PATIENTS: Twenty four adult patients undergoing scoliosis correction. INTERVENTIONS: Before the end of surgery, patients received either intravenous clonidine 0.3 micrograms/kg/hr and fentanyl 25 micrograms/kg (after an hourly dose of clonidine 2.5 micrograms/kg) or intrathecal morphine 0.3 mg. A saline infusion was administered to patients receiving morphine intrathecally. MEASUREMENTS AND MAIN RESULTS: Pain and sedation scores, hemodynamic data, and blood gases were collected in the recovery room at tracheal extubation and then every 2 hours for the next 14 hours. Tracheal extubation was performed at the same time in both groups (i.e., an average of 4 hours after the analgesic regimens were started). Intrathecal morphine provided a mean score of 20 mm on a visual analog scale ranging from 0 mm (no pain) to 100 mm (severe pain), but it resulted in increased PaCO2 at extubation (44 +/- 7 mmHg) and 2 hours later (42 +/- 7 mmHg). PaCO2 was greater than 50 mmHg in four patients receiving intrathecal morphine. Fentanyl-clonidine resulted in equipotent analgesia but was accompanied by sedation (sleeping but arousal by light tactile stimulation) and moderate hypotension (up to 69 +/- 9 mmHg for mean arterial pressure). CONCLUSIONS: This study shows that there is a major risk of respiratory depression with a single intrathecal dose of morphine 0.3 mg to control postoperative pain after scoliosis surgery. Systemic clonidine-fentanyl may be a possible approach to the postoperative pain treatment of this surgery.

Adult↗

Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance.

The nonopioid actions of spinal dynorphin may promote aspects of abnormal pain after nerve injury. Mechanistic similarities have been suggested between opioid tolerance and neuropathic pain. Here, the hypothesis that spinal dynorphin might mediate effects of sustained spinal opioids was explored. Possible abnormal pain and spinal antinociceptive tolerance were evaluated after intrathecal administration of [D-Ala(2), N-Me-Phe(4), Gly-ol(5)]enkephalin (DAMGO), an opioid mu agonist. Rats infused with DAMGO, but not saline, demonstrated tactile allodynia and thermal hyperalgesia of the hindpaws (during the DAMGO infusion) and a decrease in antinociceptive potency and efficacy of spinal opioids (tolerance), signs also characteristic of nerve injury. Spinal DAMGO elicited an increase in lumbar dynorphin content and a decrease in the mu receptor immunoreactivity in the spinal dorsal horn, signs also seen in the postnerve-injury state. Intrathecal administration of dynorphin A(1-17) antiserum blocked tactile allodynia and reversed thermal hyperalgesia to above baseline levels (i.e., antinociception). Spinal dynorphin antiserum, but not control serum, also reestablished the antinociceptive potency and efficacy of spinal morphine. Neither dynorphin antiserum nor control serum administration altered baseline non-noxious or noxious thresholds or affected the intrathecal morphine antinociceptive response in saline-infused rats. These data suggest that spinal dynorphin promotes abnormal pain and acts to reduce the antinociceptive efficacy of spinal opioids (i.e., tolerance). The data also identify a possible mechanism for previously unexplained clinical observations and offer a novel approach for the development of strategies that could improve the long-term use of opioids for pain.

Analgesics↗

Sedative infusions during local and regional anesthesia: a comparison of midazolam and propofol.

STUDY OBJECTIVE: To compare the intraoperative effects and recovery characteristics when either midazolam or propofol was used for sedation during local or regional anesthesia. DESIGN: Open-label, randomized study with blinded observer assessing recovery data. SETTING: Outpatients undergoing elective surgical procedures under local or regional anesthesia at Stanford University Hospital, Stanford, California. PATIENTS: Sixty-eight consenting, unpremedicated ASA physical status I, II, or III patients. INTERVENTIONS: After achieving adequate analgesia with local anesthetic solutions, patients were administered a loading dose of either midazolam (4.2 +/- 1.4 mg) or propofol (69 +/- 23 mg) followed by a variable-rate maintenance infusion equal to 8.6 +/- 5.4 mg/h or 265 +/- 185 mg/h, respectively, to maintain a stable level of sedation during the operation. MEASUREMENTS AND MAIN RESULTS: Intraoperative assessments included level of sedation, as well as cardiovascular and respiratory status, at 1- to 5-minute intervals during the operation. Postoperatively, recovery of cognitive and psychomotor function was assessed using analog scales and the digit-symbol substitution test. The overall quality of intraoperative sedation was similar in the two sedative treatment groups. Although midazolam produced less pain on injection and more effective intraoperative amnesia, use of propofol was associated with less postoperative sedation, drowsiness, confusion, clumsiness, and amnesia, as well as more rapid recovery of cognitive function. However, discharge times were similar in the two sedative treatment groups. CONCLUSIONS: Propofol infusion is a clinically useful alternative to midazolam for sedation during ambulatory surgery under local or regional anesthesia.

Adult↗

Intraoperative transcranial electrical motor evoked potential monitoring during spinal surgery under intravenous ketamine or etomidate anaesthesia.

Motor evoked potentials (MEPs), monitoring the motor function directly, are superior to somatosensory evoked potentials (SSEPs) in monitoring the motor system during spinal surgery. Reliable MEPs are difficult to elicit under normal anaesthesia. Using intravenous anaesthesia with either ketamine or etomidate infusion, we performed intraoperative MEP monitoring in 12 spinal operations for 11 cases from February 1992 to May 1992. For anaesthesia, ketamine was used in 5, etomidate in 7, fentanyl was supplemented in all, muscle relaxation at 30% to 50% of pre-anaesthetic muscle power was maintained with atracurium or vencuronium infusion. Transcranial bipolar electrical stimulation was used to induce MEPs. Concomitant SSEP monitoring was performed in 3. No significant anaesthesia related side effects were noted except one episode of unpleasant dream occurred in the ketamine anaesthesia group. Successful monitoring was achieved in 10 sessions. In 5 of which warning to the surgeons was made due to sudden MEP deterioration, which recovered followed by definite management in four and persisted in one. In the other 5 sessions, no warning was made due to stationary or gradual change in MEPs. Bilateral two-channel recordings were used in 3 sessions. In 2 of which unilateral transient change was noted. Loss of SSEPs was noted in one despite unchanged MEPs, in whom only new sensory deficits occurred postoperatively. Compared to the baseline MEPs in terms of latency and amplitude, the final MEPs improved in 5 sessions, did not change significantly in 4 sessions, deteriorated in one session, and were correlated well with the immediate postoperative motor status.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗