Anti-cancer properties of phenolics from apple waste on colon carcinogenesis in vitro.

Colorectal cancer is one of the most common cancers in Western countries. The World Health Organisation identifies diet as a critical risk factor in the development and progression of this disease and the protective role of high levels of fruit and vegetable consumption. Several studies have shown that apples contain several phenolic compounds that are potent anti-oxidants in humans. However, little is known about other beneficial properties of apple phenolics in cancer. We have used the HT29, HT115 and CaCo-2 cell lines as in vitro models to examine the effect of apple phenolics (0.01-0.1% apple extract) on key stages of colorectal carcinogenesis, namely; DNA damage (Comet assay), colonic barrier function (TER assay), cell cycle progression (DNA content assay) and invasion (Matrigel assay). Our results indicate that a crude extract of apple phenolics can protect against DNA damage, improve barrier function and inhibit invasion (p<0.05). The anti-invasive effects of the extract were enhanced with twenty-four hour pretreatment of cells (p<0.05). We have shown that a crude apple extract from waste, rich in phenolic compounds, beneficially influences key stages of carcinogenesis in colon cells in vitro.

Moving research into community settings in the CSAT methamphetamine treatment project: the coordinating center perspective.

The CSAT Methamphetamine Treatment Project (MTP) has been established to conduct a ground-breaking exercise in bringing research into a closer relationship with community-based treatment service organizations. In this article, some of the opportunities and challenges faced by the MTP coordinating center as it has attempted to bring research into community treatment organizations are described. Initially, there has been an active, energetic effort to design the study protocol, focus the activities of the project, and prioritize the tasks to be accomplished. The methods for training the research staff and monitoring the conduct of the research in the community sites are described. A number of observations have been made about the different "cultures and values" of the researchers and the seven clinical organizations where the project has been conducted. The myriad mistakes made and lessons learned about how to conduct a rigorous randomized clinical trial in community treatment organizations may be important for future research-treatment efforts. There has been a wealth of experience gained in the first year of this project that may be of use as efforts move forward to reduce the gap between research and practice.

The matrix model of outpatient stimulant abuse treatment: history and description.

The Matrix model was originally developed in response to the cocaine epidemic of the 1980s. The program consists of relapse prevention groups, education groups, social support groups, individual counseling, and urine and breath testing delivered in a structured manner over a 16-week period. The treatment is a directive, nonconfrontational approach which focuses on current issues and behavior change. Several evaluations of the model have supported its usefulness and efficacy with methamphetamine (MA) users. Methamphetamine users appear to respond to treatment similarly to cocaine users and many continue to show improvements at follow-up.

Addiction pharmacotherapy 2000: new options, new challenges.

There are many indicators that substance abuse research and treatment are going to become better integrated. Hopefully, this development will produce new treatment options and will improve access and effectiveness of care. Among the most significant factors in this period of change are the advances in addiction pharmacotherapy. For the treatment of alcoholism, disulfiram has been joined by naltrexone, and soon acamprosate will be added to the list of available pharmacotherapies. Individuals with opiate dependence who, for 25 years, were limited to a single medication (methadone) now have LAAM as an available treatment. Furthermore, there is eager anticipation that buprenorphine/naloxone will bring many more opiate users into treatment since it appears that this medication will be available to doctors outside the traditional narcotics treatment program settings. Other opiate addiction treatment options, including sustained-release naltrexone and lofexidine, are in active development. The greatest area of challenge for pharmacotherapy research is the search for stimulant addiction medications. NIDA has extensive efforts underway to discover/develop medicines that can help in the treatment of cocaine and methamphetamine users. During the next decade, those who embrace these new treatments and integrate them into standard care will offer their patients the best chance for recovery.

A 3-year progress report on the implementation of LAAM in the United States.

AIMS: LAAM, a long-acting opioid agonist, was approved by the US Food and Drug Administration in 1993 for use in licensed narcotic treatment programs. These programs have the exclusive authority in the United States to dispense methadone and LAAM for the treatment of opiate dependence. The purpose of this report is to describe the course of LAAM's implementation and to document some of the factors that have influenced the time course and extent of this process. DESIGN: Narcotic treatment programs approved for LAAM use were contacted by telephone at three timepoints following the FDA approval of LAAM in 1993. FINDINGS: Regulatory hurdles have been the most significant factor in slowing the use of LAAM. Some clinics have enthusiastically moved LAAM into mainstream use with great success. At other clinics LAAM implementation has been impeded by staff resistance and management reluctance. Some specific clinical practices, such as provision of adequate dose levels and flexible dosing practices, appear to be associated with superior clinical response, but issues of staff and organizational attitude toward the new medication are probably the most important impediments to a more positive response. CONCLUSIONS: The tasks involved with introducing a new opiate agonist treatment into mainstream use in the United States are numerous and complex. Clinical policies, fiscal issues and regulatory factors must all be addressed. The introduction of LAAM into the treatment system provides some useful lessons as other new addiction pharmacotherapies are moved into mainstream use.

Outpatient non-opioid detoxification for opioid withdrawal. Who is likely to benefit?

The authors examined characteristics of successful completers of an outpatient clonidine/oxazepam detoxification procedure for opioid dependence. Of 215 initial applicants, 167 received medication, and 65 successfully completed by taking a dose of naltrexone. Those who completed were more likely to have last used an opioid other than heroin, to be heroin smokers, rather than intravenous users, to have used benzodiazepines in the 30 days before treatment, and to have abstained from opioids for a longer time before presenting for treatment. New users (for less than 2 years) did no better than those using longer than 2 years. These findings may help in the continued refinement of patient placement criteria.

Overdose, suicide attempts and death among a cohort of naltrexone-treated opioid addicts.

In a study evaluating naltrexone with either an intensive psychosocial protocol or standard community treatment for opioid dependence, 13 of 81 subjects overdosed within a 12-month period of study participation. There were four fatalities, one of which was a suicide. Among the nine nonfatal overdoses, there were four suicide attempts. Characteristics of subjects and naltrexone-taking are described.

Differential activation of microglia and astrocytes following trimethyl tin-induced neurodegeneration.

We have investigated the response of astrocytes and microglia to trimethyl tin intoxication in the septum, hippocampus, olfactory bulb, and pyriform cortex of the rat. Microglia were studied qualitatively using lectin histochemistry, and astrocytes were examined both qualitatively with immunohistochemistry, and quantitatively using an immunoassay for glial fibrillary acidic protein. Our results show that activated microglia first appeared 2 days after trimethyl tin intoxication in the lateral septum and hippocampus. Four days after trimethyl tin intoxication, the same regions revealed a most intense microglial reaction characterized by microglial hypertrophy and the formation of phagocytic clusters. By day 7, microglial activation in the septum and hippocampus had lessened, suggesting that the cells were reverting to the resting phenotype. The microglial response in the pyriform cortex and olfactory bulb, while being later in onset than in the septum and hippocampus, showed a similar progression of microglial changes reaching maximal intensity 7 days after trimethyl tin intoxication. Significant increases in the expression of glial fibrillary acidic protein were observed in all regions examined and typically occurred after microglial activation was already underway. We conclude that microglial and astroglial reactions which occur in response to trimethyl tin-induced neuronal necrosis are separated in time, with microglial activation preceding astrogliosis. In addition, our study stresses the importance of microglia as an endogenous source of CNS macrophages, and illustrates the merit of histochemical analysis with microglial markers for the early delineation of neurotoxicant-induced brain damage.

An intensive outpatient approach for cocaine abuse treatment. The Matrix model.

The Matrix model of outpatient treatment was developed during the 1980s in response to an overwhelming demand for cocaine abuse treatment services. The model was constructed using components based upon empirically supported findings from the substance abuse research field. Over the course of development, data were collected on the treatment model and the model was modified based upon empirical evaluation. A pilot study comparing the Matrix outpatient model with an inpatient hospital treatment program produced preliminary support for the clinical utility of the model. An open trial comparing publicly and privately funded patients demonstrated that patients with fewer resources were more difficult to engage and retain in this model of outpatient treatment. In a controlled trial, a clear positive relationship was documented between duration and amount of treatment involvement in the Matrix model and positive outcome at 1 year. Due to a variety of methodological issues, the study was not able to answer definitively the question of clinical efficacy. In all of these studies, patients treated with the Matrix model demonstrated statistically significant reductions in drug and alcohol use and improvements in psychological indicators. This body of work, along with the public acceptance the model has received in the treatment community, support the usefulness of this intensive outpatient approach for cocaine abuse. Further research is underway to provide additional controlled information on the value of this treatment approach.

Cocaine abuse among methadone maintenance patients: are there effective treatment strategies?

Cocaine abuse among patients in methadone maintenance treatment has substantially increased in the past decade. No standard treatment approaches exist to address this problem. Empirical evidence has been collected on the effectiveness of several categories of techniques for treating this problem, including pharmacotherapies, behavioral methods (contingency management and relapse prevention), and methadone dose adjustment. Data on the effectiveness of these techniques is summarized. In addition, other treatment interventions that may be efficacious for this population, including day treatment and sober-living facilities, are described. Finally, methadone clinic management procedures that may aid in the reduction of cocaine abuse by methadone patients are discussed. Although many of these efforts are in early stages of evaluation, there are some reasons for optimism in the development of treatment for these patients.

The Matrix model of outpatient stimulant abuse treatment: evidence of efficacy.

The current study examined the effectiveness of Matrix outpatient stimulant treatment. We associated 146 subjects' in-treatment abstinence data, treatment lengths, and weekly treatment activities to their 6-month abstinence outcomes as part of an interim analysis of a NIDA treatment demonstration project. Results indicated that the pretreatment subject characteristics of ethnicity and drug of choice significantly associated with treatment outcome using Matrix model treatment. Findings also demonstrated a treatment dose/abstinence response such that those who received longer Matrix treatment episodes demonstrated better abstinence outcomes. Further, in-treatment abstinence status and treatment length significantly associated with drug use status at follow-up. This set of findings provides evidence for the value of Matrix treatment and allows for these outcome data to be compared with reports on recent psychosocial treatments for stimulant dependence. This study also provides direction for evaluating longer term effectiveness for these types of drug treatments.

Intramedullary connections of the gastric region in the solitary nucleus: a biocytin histochemical tracing study in the rat.

The local circuit neurons in the solitary nucleus that form part of a gastro-gastric vago-vagal reflex were examined using a biocytin/avidin-peroxidase histochemical tracing method in the male Long-Evans rat. Iontophoretic deposits of very small amounts of biocytin were made into the ventral commissural nucleus of the solitary tract (vcNTS) where the excitatory neuronal response to antral distension was recorded. The tracing study revealed substantial axonal projections from the vcNTS to the immediately subjacent dorsal motor nucleus of the vagus (DMN) as well as the parvocellular reticular formation (pcRF). Some axons also appeared to terminate on neurons of the nucleus retroambiguus (nRAm) in the same coronal plane as the injection site. Labeled NTS neurons in the immediate area of the injection site revealed a clear horizontally-oriented pattern of dendrites, some of which extended from the midline to the solitary tract. Some of these dendrites could be found within the walls of arterioles, the central canal or in the area postrema. This finding suggests that vcNTS neurons activated by antral inflation are probably influenced by a number of other neural and chemical afferent signals.

Neurobehavioral treatment for cocaine dependency: a preliminary evaluation.

The treatment of cocaine dependency in the 1980s has required the use of a broad range of strategies. Although there are some promising approaches for treating certain aspects of the cocaine withdrawal syndrome, there is no empirical evidence that provides a clear direction to the future development of a comprehensive treatment approach. The neurobehavioral model is an initial attempt to structure information, support, and encouragement across a series of stages that are experienced by cocaine abusers as they progress through the first 6 months of their recovery. This model attempts to sequence strategies in a way that will correspond to an expected timetable of problem emergence during recovery from cocaine dependency. Individual sessions with trained therapists are used extensively to move clients through the recovery process. Relapse prevention techniques have been used extensively within a relapse prevention group format and in a standardized relapse analysis procedure. This model has been standardized into a manual that allows for replication and evaluation. Current research efforts are under way to assess the usefulness of this model as an independent treatment approach and as a framework for evaluating other potentially useful cocaine dependency treatment strategies.

Impact of antral mechanoreceptor activation on the vago-vagal reflex in the rat: functional zonation of responses.

1. Activation of gastric sensory afferents alters gastric motor and secretory function via the gastric vago-vagal reflex. In this report, we investigated in the rat the impact of gastric mechanoreceptor activation on the brain stem components of the reflex, which are located in the dorsal vagal complex (DVC), i.e. the nucleus of the solitary tract (NTS) and the subjacent dorsal motor nucleus (DMN). 2. In our extracellular recordings of single-cell activity in the DVC, we observed a relation between the response to antral distention and the location of the cell in the DVC. Specifically, cells that were excited by antral distention (ON cells) were located dorsal to those that were inhibited (OFF cells) by the same stimulus (mean depth = 536 +/- 15 and 627 +/- 14 microns for ON and OFF cells, respectively). 3. For a subset of DVC cells, the location was marked by ionophoretic ejection of Pontamine Blue from the recording barrel. Histological analysis indicated that ON cells were located in the NTS, and OFF cells were located in the ventral NTS or within the boundaries of the DMN. Together, these data led to the hypothesis that ON and OFF cells are functionally different groups of neurones, i.e. ON cells may be NTS neurones, and OFF cells may be DMN neurones. We tested this directly by employing both an intragastric balloon and a non-traumatic vagal stimulating electrode to determine whether inflation-related cells were NTS or DMN cells via orthodromic and antidromic activation, respectively. 4. Almost all ON cells (12/13) were orthodromically activated by vagal stimulation, i.e. they were NTS neurones. One ON cell was antidromically activated, and therefore was a DMN neurone. Of the twenty-eight OFF cells that were encountered, ten were classified as NTS neurones because they were orthodromically inhibited by vagal stimulation. The remaining eighteen OFF cells were orthodromically inhibited and antidromically activated (i.e. DMN neurones). Thus, our results support the hypothesis that ON and OFF cells can be functionally distinct populations of neurones, in that almost all ON cells are NTS cells and approximately 2/3 of the OFF cells are DMN neurones. 5. The response to mechanoreceptor activation was different for NTS and DMN neurones. NTS cells were activated (55%) or inhibited (45%) by balloon distention of the stomach, whereas DMN cells were almost exclusively inhibited (95%) by this stimulus. This information provides insight into the organization of excitatory and inhibitory connections of the brain stem components that mediate gastric vago-vagal reflexes.

Dorsal medullary injection of atrial natriuretic factor (ANF) excites vagal efferents and inhibits gastric motility.

Atrial natriuretic factor (ANF)-immunoreactive fibers are found in the dorsal motor nucleus of the vagus (DMN) along with receptors for that peptide. Previous investigations showed that ANF injections into the DMN did not influence cardiovascular functions. Since the DMN is largely (but not exclusively) involved with the control of gastrointestinal functions, we hypothesized that ANF may act on gastric, rather than cardiovascular vagal efferents. Injections of ANF (20 pmol rat atriopeptin III in 20 nl) into the DMN evoked a vagally dependent reduction in gastric motility. In a separate electrophysiological study, 10 of 15 (66%) antidromically identified DMN neurons were excited by micropressure-applied ANF (25-500 fmol in 50-1000 pl). We propose that ANF-containing neurons in the DMN reduce gastric motility by activating vagal efferents that synapse with inhibitory neurons in the gastric enteric nervous system.

Cocaine abuse treatment: a review of current strategies.

The treatment of cocaine abusers is a newly emerging discipline. Many of the strategies that are being developed for this purpose have been adapted from the drug and alcoholism treatment systems. These include use of established programs that are only minimally modified for cocaine abusers, such as the 28-day inpatient hospital, therapeutic community, and 12-step programs. Other approaches have created specific techniques to meet particular clinical needs of cocaine abusers, such as behavioral, pharmacologic, and nontraditional interventions. Finally, several attempts have been made to create integrated outpatient approaches that address the multiple needs of the cocaine abusers. Many of the clinical researchers conducting research on these modalities feel optimistic about the value of treatment for cocaine abusers. Many of the methods appear to have considerable promise. However, only recently have well-controlled research efforts begun to provide the information necessary for empirically based decision-making. During the next several years, outcome studies should provide an excellent set of data to guide treatment efforts. This paper reviews the treatment efforts that have been conducted, overviews the research data available, and describes some of the outcome research in progress.

Psychological approaches for the treatment of cocaine dependence--a neurobehavioral approach.

A variety of psychological approaches have been utilized for the treatment of cocaine dependence. Most information has been presented in case report format. However, several investigations have established integrated outpatient approaches which are currently being systematically evaluated. One of these approaches, the neurobehavioral model of cocaine dependency treatment establishes a clear timetable for cocaine recovery and focusses attention on four discreet areas of functioning. Strategies for addressing these areas of functioning include relapse prevention methods as well as individual therapy procedures, family systems materials, educational information, 12 step involvement and urine testing. The model constructs a comprehensive framework for facilitating involvement in recovery activities which promote positive behavior change. Use of this standardized treatment format allows for the evaluation of the treatment model. In an open trial with 486 cocaine users, a majority of subjects were retained in treatment for a clinically significant period of time and while in treatment provided urine samples indicating substantial periods of cocaine abstinence. Current research is underway to evaluate: (1) subject factors which appear to be related to successful outcome with this treatment model; (2) a controlled clinical trial to evaluate the treatment model with cocaine users using random assignment; (3) a double-blind evaluation of desipramine versus placebo and versus no medication as an adjunct to the support provided by the model.

Oxytocin excites gastric-related neurones in rat dorsal vagal complex.

1. Dorsal medullary injections of oxytocin (OT) influence gastric motor and secretory function via a vagally mediated mechanism. Thus, it was hypothesized that OT altered the firing rate of brain stem vagal neurones that were specifically related to gastric function. 2. To study this, glass microelectrode/injection pipette arrays were used to record the activity of gastric-related neurones in the dorsal vagal complex (DVC), which includes vagal sensory neurones in the nucleus tractus solitarius (NTS) and motor neurones in the dorsal motor nucleus (DMN). After identifying such a neurone, spontaneous activity was monitored before and after micropressure injection of OT and vehicle solutions from the pipettes. 3. Two methods were used to identify neurones that were related to gastric function. One method employed a gastric balloon to identify DVC neurones that were responsive to gastric inflation. The second method employed a gastric vagal stimulating electrode, which permitted the identification of gastric-related NTS and DMN cells via orthodromic or antidromic activation, respectively. 4. Twenty-four of forty-two gastric-inflation-related neurones responded to administration of OT (100-400 fmol in 100-400 pl). The majority of those responding to OT were activated by this peptide (21/24). All the cells tested (n = 13) remained sensitive to gastric inflation after administration of OT. Also, OT was found to excite the majority of cells that were identified as gastric-related NTS (nine excited; one no effect) or DMN cells (eleven excited; two no effect). 5. These studies support the hypothesis that central oxytocinergic neurones influence gastric motility and secretion by increasing the excitability of central vagal neurones in the NTS and DMN that are related to gastric function.

Activation of the bed nucleus of the stria terminalis increases gastric motility in the rat.

The diencephalic bed nucleus of the stria terminalis is known to make direct, peptide-containing axonal connections with the brainstem dorsal vagal complex, i.e., the nucleus of the solitary tract and the dorsal motor nucleus of the vagus. Given these anatomical data, one would predict that the bed nucleus, like other forebrain nuclei with similar connections, should function to alter parasympathetic autonomic functions. To examine this possibility, we activated the bed nucleus via electrical microstimulation and glutamate microinjections while monitoring gastric motility with miniature extraluminal strain gauges. We found that activation of the bed nucleus produced an increase in gastric motility that was atropine sensitive. This finding raises the possibility that the bed nucleus may be a significant forebrain regulator of gastrointestinal function.