Phenylpiperazine derivatives with selectivity for dopamine D3 receptors modulate cocaine self-administration in rats.

This study examined cocaine self-administration after pretreatments with three structurally related compounds that bind selectively to dopamine D3 receptors (D3Rs) relative to the D2 receptor subtype (D2Rs) and exhibit varying intrinsic activities in the forskolin-stimulated adenylyl cyclase assay. The compounds are: a) WC10, a D3R weak partial agonist/antagonist with 42-fold D3R:D2R selectivity, b) WC26, a 51-fold selective D3R partial agonist, c) WC44, a 23-fold selective D3R agonist. Rats were stabilized on a multiple variable-interval 60-s (VI60) schedule with alternating components of sucrose (45 mg pellets) or cocaine reinforcement (0.375 mg/kg, IV) and then tested for effects of the WC compounds (0.0, 1.0, 3.0, 5.6, or 10.0 mg/kg, IP). Another cohort was trained to self-administer cocaine (0.75 mg/kg, IV) on a VI60 schedule then tested with various doses of cocaine available (0.0-1.5 mg/kg, IV) following pretreatment with WC10 (5.6 or 10.0 mg/kg) or WC44 (10.0 mg/kg). WC10 and WC26 decreased both cocaine and sucrose reinforcement rates at the 10.0 mg/kg dose, whereas WC44 decreased only cocaine reinforcement rate at this dose. Furthermore, WC26 and WC44 increased response latency for cocaine but not sucrose. In the cocaine dose-response experiment, WC10 and WC44 flattened the dose-effect function of cocaine reinforcement rate. All compounds decreased spontaneous locomotion. WC10 and WC26 also reduced cocaine-induced locomotion. These results support the targeting of D3Rs for treatments for cocaine dependence. WC26 and WC44, in particular, show promise as they increased the latency to respond for cocaine but not sucrose, suggesting selective reduction of the motivation for cocaine.

Coherent transients in the femtosecond photoassociation of ultracold molecules.

We demonstrate the photoassociation of ultracold rubidium dimers using coherent femtosecond pulses. Starting from a cloud of ultracold rubidium atoms, electronically excited rubidium molecules are formed with shaped photoassociation pump pulses. The excited state molecules are projected with a time-delayed probe pulse onto molecular ion states which are detected in a mass spectrometer. Coherent transient oscillations of the excited state population are observed in the wings of the pump pulse, in agreement with the time-dependent solution of the Schrödinger equation of the excitation process.

Beyond the reward hypothesis: alternative functions of nucleus accumbens dopamine.

According to the dopamine (DA) hypothesis of reward, DA systems in the brain, particularly in the nucleus accumbens, are thought to directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food, water and sex, as well as various drugs of abuse. However, there are numerous problems associated with this hypothesis. Interference with accumbens DA transmission does not substantially blunt primary motivation for natural rewards such as food, but it does disrupt the propensity of animals to engage in effortful responding to obtain food. Electrophysiological and voltammetric studies indicate that novel stimuli, conditioned stimuli that predict reward, and instrumental behaviors that deliver natural rewards all act to stimulate DA activity. Accumbens DA acts as a modulator of several functions related to motivated behavior, and can influence normal and pathological cognitive function, activational aspects of motivation, anergia or psychomotor slowing in depression, the impact of conditioned stimuli, plasticity and a variety of sensorimotor functions.

Nucleus accumbens dopamine and the regulation of effort in food-seeking behavior: implications for studies of natural motivation, psychiatry, and drug abuse.

For several decades, it has been suggested that dopamine (DA), especially in nucleus accumbens, mediates the primary reinforcing characteristics of natural stimuli such as food, as well as drugs of abuse. Yet, several fundamental aspects of primary food reinforcement, motivation, and appetite are left intact after interference with accumbens DA transmission. Recent studies have shown that accumbens DA is involved in responsiveness to conditioned stimuli and activational aspects of motivation. In concurrent choice tasks, accumbens DA depletions cause animals to reallocate their choice behavior in the direction of instrumental behaviors that involve less effort. Also, an emerging body of evidence has demonstrated that the effects of accumbens DA depletions on instrumental food-seeking behavior can vary greatly depending upon the task. For example, some schedules of reinforcement are insensitive to the effects of DA depletions, whereas others are highly sensitive (e.g., large fixed ratios). Accumbens DA depletions slow the rate of operant responding, blunt the rate-facilitating effects of moderate-sized ratios, and enhance the rate-suppressing effects of very large ratios (i.e., produce ratio strain). Accumbens DA may be important for enabling rats to overcome behavioral constraints, such as work-related response costs, and may be critical for the behavioral organization and conditioning processes that enable animals to engage in vigorous responses, such as barrier climbing, or to emit large numbers of responses in ratio schedules in the absence of primary reinforcement. The involvement of accumbens DA in activational aspects of motivation has implications for energy-related disorders in psychiatry, as well as aspects of drug-seeking behavior.

Intrahepatic cholangiocarcinoma: resectability, recurrence pattern, and outcomes.

Intrahepatic cholangiocarcinoma (IHC) is a rare primary hepatic tumor of bile duct origin for which resection is the most effective treatment. But resectability, outcomes after resection, and recurrence patterns have not been well described. Patients with IHC were identified from a prospective database. Demographic data, tumor characteristics, and outcomes were analyzed. From March 1992 to September 2000, 53 patients with hepatic tumors underwent exploration and were found to have pure IHC on pathologic analysis. Patients with mixed hepatocellular and cholangiocarcinoma tumors were excluded. At exploration, 20 patients were unresectable for an overall resectability rate of 62% (33 of 53). Median survival for patients submitted to resection was 37.4 months versus 11.6 months for patients undergoing biopsy only (p = 0.006; median followup for surviving patients, 15.6 months). Actuarial 3-year survival was 55% versus 21%, respectively. Factors predictive of poor survival after resection included vascular invasion (p = 0.0007), histologically positive margin (p = 0.009), or multiple tumors (p = 0.003). After resection, 20 of 33 patients (61%) recurred at a median of 12.4 months. Sites of recurrence included the liver (14), retroperitoneal or hilar nodes (4), lung (4), and bone (2). The median disease-free survival was 19.4 months, with a 3-year disease-free survival rate of 22%. Factors predictive of recurrence were multiple tumors (p = 0.0002), tumor size (p = 0.001), and vascular invasion (p = 0.01). About two-thirds of patients who appeared resectable on preoperative imaging were amenable to curative resection at the time of operation. Although complete resection improved survival, recurrence was common. The majority of recurrences were local or regional, which may help guide future adjuvant therapy strategies.

Passive exposure to a contextual discriminative stimulus reinstates cocaine-seeking behavior in rats.

A significant problem in treating cocaine dependence is craving-induced relapse elicited by inadvertent (i.e., passive) exposure to cocaine-paired stimuli. Extinction/reinstatement of cocaine-seeking behavior in animals has been used to investigate this phenomenon. Most studies using this model have examined reinstatement by response-contingent exposure to discrete cocaine-paired stimuli. The present study expanded this research by examining passive (i.e., not contingent upon an operant response) exposure to a contextual cocaine-paired stimulus to better model craving elicited by inadvertent exposure to cocaine-associated environmental stimuli. Rats underwent daily cocaine and saline self-administration sessions that were identical to each other except for a discriminative stimulus (scented bedding) signaling cocaine availability (S+) or nonavailability (S-). Subsequently, they were placed into the self-administration chambers in the presence of neutral bedding. Reinforcement was not available and cocaine-seeking behavior (i.e., nonreinforced operant responses) was extinguished across days. Rats were then reintroduced to the S+ and S- stimuli. Presentation of the S+, but not the S-, elicited significant reinstatement of cocaine-seeking behavior. The results demonstrate that passive exposure to a contextual discriminative stimulus reinstates extinguished cocaine-seeking behavior. Furthermore, we suggest that reinstatement of cocaine-seeking behavior by passive exposure to cocaine-paired stimuli may provide a model of craving-induced relapse elicited by inadvertent exposure to a cocaine-associated environment.

Chloroquine antagonizes the proinflammatory cytokine response to opportunistic fungi by alkalizing the fungal phagolysosome.

Recent observations demonstrated that the antimalarial drug chloroquine (CQ) can kill the opportunistic fungus Cryptococcus neoformans. Since CQ blunts lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha release, it was hypothesized that this drug would also interfere with the inflammatory response to C. neoformans and Candida albicans, another fungal opportunist. CQ inhibited TNF-alpha release from peripheral blood mononuclear cells from healthy and human immunodeficiency virus-positive donors without affecting NF-kappaB activation. CQ reduced TNF-alpha mRNA levels by a pH-dependent mechanism in a manner similar to 2 unrelated alkalizing drugs (ammonium chloride and bafilomycin), which also inhibited TNF-alpha gene expression. Although CQ inhibited release of interleukin (IL)-1beta and IL-6, it did not affect IL-10 or macrophage inflammatory protein-1alpha production. Thus, CQ interferes with fungus-induced TNF-alpha expression by a mechanism that probably depends on the alkalization of endolysosomes. This contrasts with CQ's reported pH-independent inhibition of LPS-stimulated TNF-alpha release and suggests that the mechanism of CQ's anti-inflammatory effects is stimulus specific.

Survival after resection of multiple hepatic colorectal metastases.

BACKGROUND: Hepatic resection is potentially curative in selected patients with colorectal metastases. It is a widely held practice that multiple colorectal hepatic metastases are not resected, although outcome after removal of four or more metastases is not well defined. METHODS: Patients with four or more colorectal hepatic metastases who submitted to resection were identified from a prospective database. Number of metastases was determined by serial sectioning of the gross specimen at the time of resection. Demographic data, tumor characteristics, complications, and survival were analyzed. RESULTS: From August 1985 to September 1998, 155 patients with four or more metastatic tumors (range 4-20) underwent potentially curative resection by extended hepatectomy (39%), lobectomy (42%), or multiple segmental resections (19%). Operative morbidity and mortality were 26% and 1%, respectively. Actuarial 5-year survival was 23% for the entire group (median = 32 months) and there were 12 actual 5-year survivors. On multivariate analysis, only number of hepatic tumors (P = .005) and the presence of a positive margin (P = .003) were independent predictors of poor survival. CONCLUSIONS: Hepatic resection in patients with four or more colorectal metastases can achieve long-term survival although the results are less favorable as the number of tumors increases. Number of hepatic metastases alone should not be used as a sole contraindication to resection, but it is clear that the majority of patients will not be cured after resection of multiple lesions.

Chloroquine and the fungal phagosome.

The antimalarial drug chloroquine accumulates inside the macrophage phagolysosome by ion trapping where it exerts potent antifungal activity against Histoplasma capsulatum and Cryptococcus neoformans by distinct mechanisms. Chloroquine inhibits growth of H. capsulatum by pH-dependent iron deprivation, whereas it is directly toxic to C. neoformans. Clearly, clinical studies are required to document the potential therapeutic efficacy of chloroquine or related congeners as adjuvant therapy in fungal disease. Moreover, the diversity of pathogenic microorganisms inhibited and/or killed by chloroquine makes this drug an attractive candidate for prophylactic therapy.

Chloroquine interferes with lipopolysaccharide-induced TNF-alpha gene expression by a nonlysosomotropic mechanism.

Chloroquine (CQ) is a lysosomotropic weak base with over 60 years of clinical use for the treatment of malaria and rheumatologic disorders. Consistent with its anti-inflammatory properties, CQ has been shown to interfere with TNF-alpha release from mononuclear phagocytes. Because it is unclear how CQ mediates these immunomodulatory effects, we set out to elucidate its mechanism of action. CQ exhibited dose-dependent inhibition of LPS-induced TNF-alpha release from human PBMC at therapeutically attainable concentrations. Additional studies to determine the specificity of this effect showed that although CQ reduced IL-1beta and IL-6 release, secretion of RANTES was unaffected. CQ acted by reducing TNF-alpha mRNA accumulation without destabilizing its mRNA or interfering with NF-kappaB nuclear translocation or p50/p65 isoform composition of DNA-binding complexes. Intracellular cytokine staining indicated that CQ reduced TNF-alpha production pretranslationally without interfering with TNF-alpha processing or release. We utilized bafilomycin A1 pretreatment to block the pH-dependent trapping of CQ in endosomes and lysosomes. Although bafilomycin A1 alone did not interfere with TNF-alpha expression, preincubation augmented the ability of CQ to reduce TNF-alpha mRNA levels, suggesting that CQ did not act by a lysosomotropic mechanism. Using confocal microscopy, we showed that bafilomycin A1 pretreatment resulted in a dramatic redistribution of quinacrine, a fluorescent congener of CQ, from cytoplasmic vacuoles to the nucleus. These data indicate that CQ inhibits TNF-alpha gene expression without altering translocation of NF-kappaB p50/p65 heterodimers. This dose-dependent effect occurs over a pharmacologically relevant concentration range and does not require pH-dependent lysosomotropic accumulation of CQ.

EEG alpha power and alpha power asymmetry in sleep and wakefulness.

Asymmetry of waking electroencephalography (EEG) alpha power in frontal regions has been correlated with waking emotional reactivity and the emotional content of dream reports. Little is known regarding alpha asymmetry during sleep. The present study was performed to compare alpha power and alpha power asymmetry in various brain regions across states of sleep and wakefulness. Waking and sleep EEG were recorded in a group of patients undergoing polysomnographic evaluation for possible sleep disorders. Alpha EEG asymmetry in frontal and temporal regions was significantly correlated in waking versus sleep, particularly during rapid eye movement (REM) sleep. These results suggest that patterns of frontal alpha asymmetry are stable across sleep and waking and may be related to emotional reactivity during dreaming. During sleep, alpha power was highest during slow-wave sleep and lowest during REM sleep. Implications of these data for understanding the functional significance of alpha power during waking and sleeping are considered.

Hepatic cryosurgery via minilaparotomy in a porcine model: an alternative to open cryosurgery.

BACKGROUND: Cryosurgery of liver lesions is becoming increasingly accepted for the ablation of liver tumors. Attempts at laparoscopic cryosurgery have been very limited and often need to be converted to open laparotomy due to the complexity of the procedure. METHODS: Seven domestic pigs were anesthetized, and 17 small (0.7 cm mean diameter) tumor mimicking agar "lesions" were percutaneously placed in the liver. Two small subcostal incisions ( approximately 2.0 cm) were placed, and an endocavitary ultrasound transducer (with a 2. 4-mm cryoprobe mounted on it) was placed on the liver surface. Lesions were localized and directly punctured with one or two cryoprobes under ultrasound guidance, and a single 15-min freeze was undertaken. The animals were then killed, and their livers were removed and serially sectioned. RESULTS: Total time for probe placement was approximately 10 min after incisions had been made. Animals tolerated the procedure well and all survived until they were killed. No intraabdominal complications were detected at exploration. Mean cryolesion dimensions were 3.0 cm (single probe) and 3.3 cm (dual probe) (p > 0.05). Positive margins were detected in one lesion treated with a single probe, and in none of the lesions treated with dual probes. Mean margins were 0.9 cm: 1.2 cm for the single probe and dual probe techniques, respectively. Liver surrounding control agar lesions demonstrated a thin rim of necrosis, approximately 0.5 mm wide. CONCLUSIONS: We conclude that minilaparotomy is an effective, safe, and simple method for performing hepatic cryosurgery in this animal model. This minimally invasive technique may benefit a subset of patients with lesions in accessible locations. Lesions in posterior locations may not be as amenable to this technique due to deterioration of ultrasound image quality in the far field.

Interleukin-12 gene transfer results in CD8-dependent regression of murine CT26 liver tumors.

BACKGROUND: Interleukin (IL)-12 has potent antitumor effects in animal models. We hypothesized that direct transfer of the IL-12 gene to established tumors would result in tumor regression without significant toxicity. METHODS: Liver tumors were established by direct injection of CT26, a murine adenocarcinoma, into the livers of BALB/c mice, followed by three transfections with either murine IL-12, murine granulocyte-macrophage colony-stimulating factor, or luciferase cDNA using particle-mediated gene transfer. To assess the mechanism of this effect, immunohistochemical staining and depletion experiments with anti-CD4 or -CD8 antibodies were performed. RESULTS: Progressive growth of primary tumors and carcinomatosis were present by day 16 after transfection with luciferase or murine granulocyte-macrophage colony-stimulating factor. At 50 days, complete regression of tumor was evident in seven of eight IL-12-treated mice (P < .001). In IL-12-transfected livers, immunohistochemical staining revealed an increase in CD8+ T cells. Selective depletion of CD4+ or CD8+ T cells was performed before and during transfection with murine IL-12. At 50 days, 75% of control mice were tumor-free. Only 46% of CD4+ cell-depleted mice (P = .143) and 7% of CD8+ cell-depleted mice (P < .001) were tumor-free. CONCLUSIONS: IL-12 gene transfer using particle-mediated gene transfer results in complete regression of established CT26 liver tumors in 88% of mice; this effect is dependent on CD8+ T cells.

Hepatic cryoablation: US monitoring of extent of necrosis in normal pig liver.

PURPOSE: To determine the accuracy of ultrasonography (US) for prediction of hepatic tissue necrosis after cryoablation in normal pig liver. MATERIALS AND METHODS: Five normal pig livers were treated with cryoablation monitored with US. After a single freeze cycle at 50% flow capacity, the widest diameter of the cryolesion was identified and marked with wire placement (22 wires in five lesions). Livers were removed 24 hours later, and wire tracks were marked with India ink. Livers were sectioned, and the distance was measured between wire tracks and tissue necrosis caused by freezing. RESULTS: The mean volume of areas of tissue necrosis was 11.6 cm3 +/- 4.0, the mean diameter was 2.9 cm +/- 1.0, and the mean maximum diameter was 2.9 cm +/- 0.7. The mean distance between the edge of necrosis and the wire track was 1.1 mm +/- 1.4. By excluding one outlier (6.5 mm), the mean distance from the ice ball to the necrotic area was 0.8 mm +/- 0.8. Uniform necrosis of hepatic parenchyma within the cryolesion was confirmed. CONCLUSION: US can be used to predict reliably the size of the necrotic area after hepatic cryoablation in normal pig liver. Knowledge of a small but consistent underestimation of tissue necrosis is important when planning cryoablation.

Sleep-disordered breathing and neuropsychological deficits. A population-based study.

The relationship of sleep-disordered breathing (SOB) to neuropsychological deficits was investigated with cross-sectional data from the Wisconsin Sleep Cohort Study, a population-based study of the natural history of SDB. A sample of 841 employed men and women ages 30 to 60 yr was studied by overnight polysomnography to assess the frequency of apneas and hypopneas per hour of sleep (apnea-hypopnea index, AHI). Prior to overnight polysomnography, the participants were given a battery of neuropsychological tests for functionally important capacities including motor skills, attention, concentration, information processing, and memory. Principal factor analysis of all the neuro-psychological test data revealed a psychomotor efficiency and a memory factor. Multiple regression analysis showed a significant negative association between logarithmically transformed AHI (LogAHI) and psychomotor efficiency score independent of age, gender, and educational status (p = 0.017). The relationship was not explained by self-reported sleepiness. No significant relationship was seen between LogAHI and memory score. In assessing the clinical significance of mild SDB, we estimate that an AHI of 15 is equivalent to the decrement in psychomotor efficiency associated with 5 additional yr of age, or to 50% of the decrement associated with hypnosedative use.

Perivascular and intralesional tissue necrosis after hepatic cryoablation: results in a porcine model.

BACKGROUND: Cryosurgical ablation of malignant hepatic tumors is being increasingly used for definitive treatment of metastatic colorectal and primary hepatic tumors. The lack of tumor necrosis near vessels that results from inadequate freezing may contribute to local recurrence and thus limit the applications of this therapy. This study was designed to determine whether single-freeze cryoablation could cause necrosis of both the pervascular and intralesional hepatic parenchyma. METHODS: Ten pigs were treated with one 15-minute cycle of cryoablation. Five additional animals were treated with overlapping cryolesions to simulate a double freeze. After 24 hours, animals underwent reoperation with portal vein cannulation and infusion of formalin. Serial sectioning and hematoxylin and eosin staining of cryolesions were performed. RESULTS: Complete cell death was visualized within all cryolesions. There was no difference between once or twice-frozen tissue. Vessels within or adjacent to cryolesions showed necrosis of hepatic tissue up to the vessel wall. No sections revealed incomplete necrosis of perivascular hepatic parenchyma. CONCLUSIONS: Single-freeze cryoablation results in necrosis of intralesional hepatic parenchyma without added benefit from repeat freezing. Complete necrosis of the perivascular tissue suggests that cryosurgical ablation can effectively cause necrosis immediately adjacent to vessels without concerns of incomplete ablation resulting from the heat sink effect.

Automated detection and classification of sleep-disordered breathing from conventional polysomnography data.

Efficient automated detection of sleep-disordered breathing (SDB) from routine polysomnography (PSG) data is made difficult by the availability of only indirect measurements of breathing. The approach we used to overcome this limitation was to incorporate pulse oximetry into the definitions of apnea and hypopnea. In our algorithm, 1) we begin with the detection of desaturation as a fall in oxyhemoglobin saturation level of 2% or greater once a rate of descent greater than 0.1% per second (but less than 4% per second) has been achieved and then ask if an apnea or hypopnea was responsible; 2) an apnea is detected if there is a period of no breathing, as indicated by sum respiratory inductive plethysmography (RIP), lasting at least 10 seconds and coincident with the desaturation event; and 3) if there is breathing, a hypopnea is defined as a minimum of three breaths showing at least 20% reduction in sum RIP magnitude from the immediately preceding breath followed by a return to at least 90% of that "baseline" breath. Our evaluation of this algorithm using 10 PSG records containing 1,938 SDB events showed strong event-by-event agreement with manual scoring by an experienced polysomnographer. On the basis of manually verified computer desaturations, detection sensitivity and specificity percentages were, respectively, 73.6 and 90.8% for apneas and 84.1 and 86.1% for hypopneas. Overall, 93.1% of the manually detected events were detected by the algorithm. We have designed an efficient algorithm for detecting and classifying SDB events that emulates manual scoring with high accuracy.

Delayed presentation of a tracheoesophageal fistula after blunt chest trauma.

Traumatic tracheoesophageal fistula is an uncommon injury after blunt chest injury. Rapid deceleration against the steering wheel during a high-speed motor vehicle crash is the usual mechanism of injury. Previous reports document few cases of delayed diagnosis and repair of tracheoesophageal fistula. We report a case of delayed diagnosis of tracheoesophageal fistula more than 20 years after the original trauma and describe the subsequent operative repair.

Patients' medical records: whose business is it anyway?

Physicians receive many requests for medical records information: Attorneys request medical records information for court cases; colleagues request information which may assist with consultations or in the medical care of individual patients; insurers request information with respect to necessity or appropriateness of care. However, none of these scenarios prompt as many telephone calls for advice to the Office of General Counsel at State Society headquarters as does the call or letter from a patient requesting a copy of his or her medical record.