Modeling and Staging of Osteoarthritis Progression Using Serial CT Imaging and Arthroscopy.

OBJECTIVE: The objective of this study was to describe in life methods by which osteoarthritis can be staged in order to time therapeutic interventions that are relevant to osteoarthritis (OA) clinical trials. METHODS: Twenty-two sheep underwent arthroscopic meniscal destabilization to induce OA. Serial computed tomography (CT) imaging and arthroscopy were used to monitor osteoarthritis progression at 3-month intervals over 9 months. Eleven sheep received 1 intra-articular injection of hyaluronate 3 months after OA induction and another group of 11 received saline. A linear mixed model was used to define the trajectory of shape change in the medial joint compartment. Ordinal logistic regression was used to investigate the association between morphological changes and sclerosis. RESULTS: Three months after meniscal destabilization there were early bipolar chondral lesions in the medial compartment of the knee, as well as osteophytes and bone remodeling. Superficial fissures and cartilage cracks progressed to discrete areas of cartilage thinning and fibrillation on the medial tibial plateau by 6 months that became cartilage erosions by nine months. A linear mixed effect model demonstrated significant change in medial compartment length and width with over time (P < 0.05) for both groups. A significant association between severity of sclerosis and medial compartment morphology was also observed. CONCLUSIONS: The induction of osteoarthritic lesions with meniscal release model can be followed using noninvasive and minimally invasive procedures allowing for real-time decisions about redosing therapies, or other changes such as extending trial timelines without sacrificing animals to conduct assessments.

Management of critical illness with non-invasive ventilation by an Australian HEMS.

BACKGROUND: Non-invasive ventilation (NIV) therapy is widely used for the management of acute respiratory failure. The objective of this study was to investigate the current use of NIV during interhospital retrievals in an Australian physician-led aeromedical service. METHODS: We reviewed patients receiving NIV during interhospital retrieval at the Greater Sydney Area Helicopter Medical Services (GSA-HEMS) over a 14-month period. The main objectives were to describe the number of retrievals using NIV, the need for intubation in NIV patients and the effect of the therapy on mission duration. RESULTS: Over the study period, 3018 missions were reported; 106 cases (3.51%) involved administration of NIV therapy during the retrieval. The most common indication for NIV was pneumonia (34.0%). 86/106 patients received a successful trial of NIV therapy prior to interhospital transfer. 58 patients were transferred on NIV, while 28 patients had NIV removed during transport. None of these 86 patients required intubation or died, although 17/86 ultimately required intubation within 24 hours at the receiving centre. 20/106 patients required intubation at the referring hospital after a failed trial of NIV therapy. NIV was successfully used in all available transport platforms including rotary wing. Patients receiving NIV were found to have prolonged mission durations compared with other GSA-HEMS patients (222.5 vs 193 min). This increase in mission duration was largely attributable to NIV failure, resulting in a need for Rapid Sequence Intubation at the referring hospital. CONCLUSIONS: With careful patient selection, the use of interhospital NIV is feasible and appears to be safe in a retrieval system with care provided by a critical care physician.

Individual differences in gene expression of vasopressin, D2 receptor, POMC and orexin: vulnerability to relapse to heroin-seeking in rats.

Individual vulnerability to stress-induced relapse during abstinence from chronic heroin exposure is a key feature of opiate addiction, with limited studies on this topic. Arginine vasopressin (AVP) and its V1b receptor, components of the brain stress responsive systems, play a role in heroin-seeking behavior triggered by foot shock (FS) stress in rats. In this study, we tested whether individual differences in the FS-induced heroin-seeking were associated with alterations of AVP and V1b, as well as other stress responsive systems, including pro-opiomelanocortin (POMC), orexin, plasma ACTH and corticosterone, as well as dopamine D2 receptor (D2) and plasma prolactin. Sprague-Dawley rats were subjected to 3-hour intravenous heroin self-administration (SA) and then tested in extinction, and FS-induced and heroin priming-induced reinstatements. The rats that self-administered heroin were divided into high and low reinstatement responders induced by FS (H-RI; L-RI). Over SA sessions, both the H-RI and L-RI displayed similar active lever responding, heroin infusion and total heroin intake. Compared to the L-RI, however, the H-RI showed greater active lever responses during stress-induced reinstatement, with higher AVP mRNA levels in medial/basolateral amygdala and lower D2 mRNA levels in caudate putamen. However, heroin priming resulted in similar reinstatement in both groups and produced similarly low POMC and high orexin mRNA levels in hypothalamus. Our results indicate that: 1) enhanced amygdalar AVP and reduced striatal D2 expression may be related to individual vulnerability to stress-induced reinstatement of heroin- seeking; and 2) heroin abstinence-associated alterations of hypothalamic orexin and POMC expression may be involved in drug priming-induced heroin-seeking.

Cue-induced renewal of heroin place preference: involvement of the basolateral amygdala.

It is well established that re-exposure to a context paired with the effects of drugs of abuse can renew extinguished drug seeking behavior. A context, however, typically includes several stimuli, which may differ in their ability to control drug-oriented behaviors. Hence, the primary objective of this study was to assess whether a heroin-induced place preference could be recovered by re-exposure to a contextual stimulus that was part of the conditioning context before extinction. The second objective was to explore the role of the basolateral nucleus of the amygdala (BLA) in this conditioned effect. Male Sprague-Dawley rats were injected with 3 mg/kg heroin and confined in a compartment that was distinguished by a variety of contextual stimuli, including a ceramic floor tile. During extinction, the floor stimulus was removed, and it was reintroduced for a drug-free test of preference. A control experiment evaluated the unconditioned preference for the floor stimulus. It was found that reintroduction of the floor stimulus caused the recovery of heroin place preference. This effect was not observed in rats infused in the BLA with muscimol (0.03 nmol) and baclofen (0.3 nmol) just prior to the test. These data suggest that an extinguished heroin place preference can be renewed by a contextual tactual stimulus that was part of the conditioning context, and that this process requires an intact BLA.

The effects of acute and chronic steady state methadone on memory retrieval in rats.

RATIONALE: Although widely prescribed to treat opioid addiction, little is known about the possible side effects of methadone on memory functions. OBJECTIVES: The aim of this study is to compare the effects of acute and chronic methadone on memory retrieval in rats and to explore the selectivity of possible deficits. METHODS: Administration of acute (0, 1.25, 2.5, and 5 mg/kg SC) and chronic steady state methadone (0, 10, 30, and 55 mg/kg/day SC by osmotic mini-pump) was tested on recall of three different types of information: stimulus-reward (10-arm parallel maze), stimulus-response (8-arm radial maze), and stimulus-stimulus (Barnes maze). Acute and steady state methadone doses were also compared on tests of locomotor activity and reactivity to aversive stimuli (i.e., swimming and acoustic startle). RESULTS: In the stimulus-reward task, acute methadone impaired performance as a result of severe depression of locomotion. This motor deficit, however, was modulated by the motivational valence of environmental stimulation. In fact, acute methadone did not eliminate forced swimming behavior. In the stimulus-response and stimulus-stimulus tasks, accuracy was impaired independently of direct motor deficits, but rats were hyper-reactive to aversive stimulation and, in fact, 5 mg/kg enhanced acoustic startle. Importantly, chronic steady state methadone did not affect accuracy of memory retrieval, did not depress motor or swimming activity, and did not change startle reactivity. CONCLUSION: Only acute methadone impaired accuracy and/or performance on three tests of memory retrieval. These findings in rats suggest that memory deficits reported in methadone-maintained individuals may not be directly attributable to methadone.

Treatment-like steady-state methadone in rats interferes with incubation of cocaine sensitization and associated alterations in gene expression.

In a previous study, steady-state methadone treatment was found to prevent associative cocaine learning, as well as related decreases in mRNA expression of preprohypocretin/preproorexin (ppHcrt) in the lateral hypothalamus (LH) and dopamine D2 receptor (DR2) in the caudate-putamen (CP), and increases in mu-opioid receptor in the ventral striatum of rats. To investigate whether the same regimen of methadone exposure could prevent the incubation of cocaine sensitization and related alterations in gene expression, male Sprague-Dawley rats received 45 mg/kg/day steady-dose "binge" cocaine administration (IP) for 14 days followed by mini-pumps releasing 30 mg/kg/day methadone (SC). After 14 days of methadone, and a subsequent 10-day drug-free period, all rats were tested for sensitization (cocaine test dose: 15 mg/kg) and brain tissue was collected to quantify mRNA expression. Rats exposed to cocaine displayed cocaine-induced stereotypy at test, as well as enhanced ppHcrt mRNA in the LH and reduced DR2 mRNA in the CP. Importantly, these alterations were significantly reduced in rats treated with methadone following cocaine. These results suggest that steady-state methadone can interfere with the incubation of neuroadaptations underlying changes in behavioral responses to cocaine and cocaine-associated stimuli, and that these effects can be observed even after withdrawal from methadone.

Animal studies trigger new insights on the use of methadone maintenance.

BACKGROUND: Although steady-state methadone (SSM) treatment is mainly used for opioid addiction, some clinical studies indicate that it also reduces cocaine abuse in opioid-dependent individuals. OBJECTIVE/METHODS: To present evidence suggesting that SSM may be useful in the treatment of cocaine addiction without pre-existing opioid dependence. We review studies in animals investigating the effects of SSM on behaviors motivated by cocaine and on cocaine-induced alterations of genes expression in the rat brain. CONCLUSION: SSM reduces cocaine intake, blocks cocaine seeking and normalizes expression of genes known to regulate cocaine seeking. These findings suggest that SSM could be an effective pharmacological agent to assist cocaine detoxification and prevention of relapse to cocaine abuse in individuals not co-dependent on opioid.

Unreinforced responding during limited access to heroin self-administration.

These studies were designed to explore a peculiar behavior displayed by rats during the acquisition of heroin self-administration (0.05 mg/kg/infusion) on a fixed-ratio 1 schedule of reinforcement in limited access conditions (i.e. 3 h/day). Rats trained under these conditions develop a tendency to emit extra lever presses during the time of heroin infusions (unreinforced responses). We found that a similar behavior develops in animals responding for sucrose pellets, but not for intravenous infusions of cocaine (0.5 mg/kg/infusion, 3 h/day). In sucrose trained rats, unreinforced responses emitted during the delivery of sucrose pellets was enhanced by food deprivation. In heroin trained rats, development of unreinforced responding was accompanied by an increase in responding for heroin on a progressive ratio schedule, and by a reduction of the depressant action of heroin (3 mg/kg, SC) on locomotor activity. On the basis of these findings, we concluded that unreinforced responding during heroin self-administration reflects a change in the motivation to obtain the drug, as well as a reduced sensitivity the motor impairing action of heroin. This suggests that acquisition of heroin self-administration is regulated by a balance between drug effects that promote and limit heroin intake.

Involvement of arginine vasopressin and V1b receptor in heroin withdrawal and heroin seeking precipitated by stress and by heroin.

A previous study has shown that the stress responsive neurohormone arginine vasopressin (AVP) is activated in the amygdala during early withdrawal from cocaine. The present studies were undertaken to determine whether (1) AVP mRNA levels in the amygdala or hypothalamus, as well as hypothalamic-pituitary-adrenal (HPA) activity, would be altered during chronic intermittent escalating heroin administration (10 days; 7.5-60 mg/kg/day) or during early (12 h) and late (10 days) spontaneous withdrawal; (2) foot shock stress would alter AVP mRNA levels in the amygdala or hypothalamus in rats withdrawn from heroin self-administration (7 days, 3 h/day, 0.05 mg/kg/infusion); and (3) the selective V1b receptor antagonist SSR149415 (1 and 30 mg/kg, intraperitoneal) would alter heroin seeking during tests of reinstatement induced by foot shock stress and by heroin primes (0.25 mg/kg), as well as HPA hormonal responses to foot shock. We found that AVP mRNA levels were increased during early spontaneous withdrawal in the amygdala only. This amygdalar AVP mRNA increase was no longer observed at the later stage of heroin withdrawal. Foot shock stress increased AVP mRNA levels in the amygdala of rats withdrawn from heroin self-administration, but not in heroin naïve rats. Behaviorally, SSR149415 dose-dependently attenuated foot shock-induced reinstatement and blocked heroin-induced reinstatement. Finally, SSR149415 blunted the HPA activation by foot shock. Together, these data in rats suggest that stress responsive AVP/V1b receptor systems (including the amygdala) may be critical components of the neural circuitry underlying the aversive emotional consequences of drug withdrawal, as well as the effect of negative emotional states on drug-seeking behavior.

High-dose methadone maintenance in rats: effects on cocaine self-administration and behavioral side effects.

It has been demonstrated that high-dose methadone maintenance is efficacious in reducing cocaine abuse in opioid-dependent individuals, but it is not clear whether this is caused by an action of methadone on the direct reinforcing properties of cocaine or on cocaine seeking. Also, it is not clear whether high-dose methadone maintenance may induce behavioral side effects, which could limit its clinical use. Here, we report that high-dose methadone maintenance (20-40 mg/kg/day) does not reduce, and even enhances cocaine (10-30 mg/kg, i.p.)-induced elevation in dopamine concentration in the ventral striatum measured by in vivo microdialysis. In parallel, however, rats maintained on high-dose methadone (30 mg/kg/day) seek and consume significantly less cocaine than controls when tested for intravenous cocaine (0.5 mg/kg/infusion) self-administration on a progressive ratio schedule of reinforcement. This reduction in cocaine self-administration does not result from impaired sensory-motor functioning as rats maintained on high-dose methadone show normal locomotor activity. Furthermore, the reduction in responding for cocaine does not seem to result from general behavioral deficits as male rats maintained on high methadone doses respond normally to palatable food and thermal pain, although their sexual responses to receptive females are greatly suppressed. Taken together, these results from studies in rats support the usefulness of larger doses of methadone to reduce severe cocaine abuse in opioid-dependent individuals and possibly in the management of pure-cocaine addiction.

Effects of high-dose methadone maintenance on cocaine place conditioning, cocaine self-administration, and mu-opioid receptor mRNA expression in the rat brain.

Methadone maintenance at appropriate doses can effectively reduce cocaine abuse in heroin-dependent individuals. In the present studies, we investigated the effect of high-dose methadone maintenance cocaine conditioned place preference (CPP) and cocaine intravenous self-administration. Rats implanted with methadone-filled osmotic mini-pumps (20 and 55 mg/kg/day, SC) and conditioned with cocaine (1, 5, and 20 mg/kg, i.p.) did not express cocaine CPP. Similarly, rats implanted with methadone pumps (55 mg/kg/day) after cocaine conditioning (20 mg/kg) displayed neither spontaneous nor cocaine-precipitated (20 mg/kg, i.p.) CPP. In contrast, methadone maintenance (30 and 55 mg/kg/day, SC) did not alter the intravenous self-administration (continuous schedule of reinforcement) of various doses of cocaine (0.1, 0.5, and 2.0 mg/kg/inf). To explore neuropharmacological interactions between methadone maintenance and cocaine conditioning, we quantitatively measured mRNA levels of mu-opioid receptor (MOR) and proopiomelanocortin genes 10 days after methadone maintenance. MOR mRNA levels in both the nucleus accumbens core and frontal cortex were significantly elevated in rats exposed to cocaine during CPP conditioning. However, upregulation of MOR mRNA levels in the nucleus accumbens core were reduced by methadone maintenance in a dose-dependent manner. In conclusion, our results suggest that high-dose methadone maintenance does not alter the direct reinforcing effect of cocaine, but blocks spontaneous and cocaine-precipitated cocaine-seeking, possibly by preventing MOR alterations in the nucleus accumbens core induced by cocaine conditioning.

Incurable colorectal carcinoma: the role of surgical palliation.

About 20 per cent of patients with carcinoma of the colon or rectum present with metastatic disease. Surgeons are frequently asked to consider resection or other operative procedures in these patients for palliation. We performed this review to determine whether patients presenting with known metastatic colorectal cancer derive benefit from surgical intervention. We performed a retrospective review of all patients with M1 carcinoma of the colon or rectum who were identified from the University of Mississippi Medical Center Cancer Registry from April 1985 through February 2003. Patients who underwent hepatic and/or pulmonary resection with curative intent were excluded from analysis, as were patients with metachronous metastases. Eighty patients with M1 colorectal cancer who did not undergo surgery with curative intent were identified, and in 74 of these, complete medical records and follow-up were available. Forty-nine of the 74 patients (66%) underwent an operation, and 25 were managed nonoperatively. Indications for surgery included bowel obstruction, active hemorrhage, severe anemia from gastrointestinal bleeding with requirement for blood transfusions, intractable pain, and perforation of the colon. Average survival was 11.2 months for operative patients versus 6.5 months for nonoperative patients (P < 0.05). Thirty-six patients who underwent resectional procedures had a postoperative hospitalization of 7.5 days and a median survival of 11.5 months. Thirteen patients who had a nonresectional procedure had an average postoperative stay of 9 days and a median survival of 4 months. Median survival in those who did not undergo an operation was 4.8 months. Although metastatic colorectal carcinoma cannot usually be cured by surgical intervention, many patients who present with metastatic disease will benefit from palliative operations with relatively short hospitalizations and reasonable survival. Those who are not candidates for resection of the primary tumor have shorter survival times. Surgery can alleviate many of the distressing symptoms in patients with metastatic colorectal carcinoma.