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Background: Recent evidence [Surg Endosc (2007) 21: 602-606] demonstrates that intraperitoneal bupivacaine administered as an aerosol via a special catheter is safe and significantly decreases postoperative pain in laparoscopic surgery. We currently use the Insuflow device (Lexion Medical) routinely to warm and humidify gas in laparoscopic surgery. The purpose of this study is to determine whether using bupivacaine instead of water in existing technology already in use (Insuflow) will result in decreased postoperative pain, without increasing operative time or cost.Methods: Using a double-blind methodology, 50 patients undergoing elective outpatient laparoscopic cholecystectomy were randomized to a study drug: either 10 ml of 0.5% bupivacaine (50 mg) or 10 ml of sterile water. The study drug was injected into the Insuflow in the standard fashion and the operation commenced routinely. No perioperative nonsteroidal anti-inflammatory drugs were used. Using a standard 0-10 pain-scoring scale, patients were assessed by perioperative nurses at 1 and 2 h postoperatively. Pain was again assessed at 24 h by telephone interview, along with the number of narcotic oral analgesics used in the first 24 h.Results: Fifty patients were randomized, 25 in each group; the groups were comparable. All patients completed the study and 100% follow-up was obtained. All patients were discharged the same day and there were no significant complications in either group, and specifically no complications attributed to bupivacaine or use of the Insuflow device. There were no differences in pain at 1 and 2 h. There was less pain in the bupivacaine group at 24 h, but this was not statistically significant (P = 0.055).Conclusions: Bupivacaine use in the Insuflow device is safe. No significant differences in postoperative pain were noted in this study compared to using water. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Theory and some preliminary evidence suggest that contingency management may be an effective treatment strategy or adjunct to psychosocial treatment for methamphetamine use disorders. An experimentally rigorous investigation on the topic was provided by a large multisite trial conducted under the auspices of the Clinical Trials Network of the National Institute on Drug Abuse. METHOD: The authors report data on 113 participants who were diagnosed with methamphetamine abuse or dependence. They were randomly assigned to receive 12 weeks of either treatment as usual or treatment as usual plus contingency management. Urine samples were tested for illicit drugs, and breath samples were tested for alcohol. The reinforcers for drug-negative samples were plastic chips, some of which could be exchanged for prizes. The number of plastic chips drawn increased with each week of negative samples but was reset to one after a missed or positive sample. RESULTS: The participants in both groups remained in treatment for equivalent times, but those receiving contingency management in addition to usual treatment submitted significantly more negative samples, and they were abstinent for a longer period of time (5 versus 3 weeks). CONCLUSIONS: These results suggest that contingency management has promise as a component in treatment strategies for methamphetamine use disorder. [ABSTRACT FROM AUTHOR]

Although it is known to be a rich source of the putative anti-cancer chemicals isothiocyanates, watercress has not been extensively studied for its cancer preventing properties. The aim of this study was to investigate the potential chemoprotective effects of crude watercress extract toward three important stages in the carcinogenic process, namely initiation, proliferation, and metastasis (invasion) using established in vitro models. HT29 cells were used to investigate the protective effects of the extract on DNA damage and the cell cycle. The extract was not genotoxic but inhibited DNA damage induced by two of the three genotoxins used, namely hydrogen peroxide and fecal water, indicating the potential to inhibit initiation. It also caused an accumulation of cells in the S phase of the cell cycle indicating (possible) cell cycle delay at this stage. The extract was shown to significantly inhibit invasion of HT115 cells through matrigel. Component analysis was also carried out in an attempt to determine the major phytochemicals present in both watercress leaves and the crude extract. In conclusion, the watercress extract proved to be significantly protective against the three stages of the carcinogenesis process investigated. [ABSTRACT FROM AUTHOR]

Milk has been shown to contain a specific fraction of extracellular particles that are reported to resist digestion and are purposefully packaged with lipids, proteins, and nucleic acids to exert specific biological effects. These findings suggest that these particles may have a role in the quality of infant nutrition, particularly in the early phase of life when many of the foundations of an infant's potential for health and overall wellness are established. However, much of the current research focuses on human or cow milk only, and there is a knowledge gap in how milk from other species, which may be more commonly consumed in different regions, could also have these reported biological effects. Our review provides a summary of the studies into the extracellular particle fraction of milk from a wider range of ruminants and pseudo-ruminants, focusing on how this fraction is isolated and characterised, the stability and uptake of the fraction, and the reported biological effects of these fractions in a range of model systems. As the individual composition of milk from different species is known to differ, we propose that the extracellular particle fraction of milk from non-traditional and minority species may also have important and distinct biological properties that warrant further study.

Calcaneal osteomyelitis can be a debilitating disease if proper treatment protocols are not initiated. This literature review details the epidemiology, clinical, diagnostic, and prognostic factors, and medical management in those who developed this disease.

Background: Infective endocarditis (IE) is associated with significant morbidity and mortality. Non-adherence to IE guidelines and recommendations is frequent, and may adversely impact patient outcomes., Aim: To assess the impact of non-adherence to components of existing IE guidelines and recommendations on a composite outcome consisting of any of the following: mortality, unplanned cardiac surgery, embolic event or relapse of positive blood culture within six months of diagnosis., Methods: A single centre, retrospective cohort study., Results: Amongst 157 patients, there was inconsistent adherence to: initial diagnosis of an infective condition (87%), timely administration of antimicrobial therapy (82%), appropriateness of predominant antimicrobial regime (94%), appropriate management of the portal of entry (86%), multidisciplinary input (75%), end of antimicrobial therapy repeat echocardiography (60%) and adherence to indications for surgery (76%). Inpatient mortality was 12.1% (n = 19) and the composite adverse outcome occurred in 36 (22.9%) patients. In multivariate logistic regression analysis, infection of prosthetic device (adjusted odds ratio [95% confidence interval]; 2.43 [1.07-5.50]) and non-adherence to surgical guidelines (aOR 3.67 [1.60-8.47]) were significantly associated with an adverse outcome., Conclusions: Our data suggests that adherence to differing components of IE management guidelines and recommendations varies and that non-adherence to surgical aspects of guidelines has the biggest impact in determining outcomes., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Acquired digital fibrokeratomas are a benign soft tissue tumor with typical appearance and anatomical locations. This lesion generally occurs in middle aged males with common sites of occurrence in the digits of upper or lower extremities. Previous case studies have reported incidences of this lesion appearing on heels of middle-aged males but are generally described as giant digital fibrokeratoma based on the lesion's diameter. This case report describes an acquired digital fibrokeratoma in a pediatric female patient in an infrequent location., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The use of deer velvet antler (DVA) as a potent traditional medicine ingredient goes back for over 2000 years in Asia. Increasingly, though, DVA is being included as a high protein functional food ingredient in convenient, ready to consume products in Korea and China. As such, it is a potential source of endogenous bioactive peptides and of 'cryptides', i.e. bioactive peptides enzymatically released by endogenous proteases, by processing and/or by gastrointestinal digestion. Fermentation is an example of a processing step known to release bioactive peptides from food proteins. In this study, we aimed to identify in silico bioactive peptides and cryptides in DVA, before and after fermentation, and subsequently to validate the major predicted bioactivity by in vitro analysis., Methods: Peptides that were either free or located within proteins were identified in the DVA samples by liquid chromatography-tandem mass spectrometry (LC-MS/MS) followed by database searching. Bioactive peptides and cryptides were identified in silico by sequence matching against a database of known bioactive peptides. Angiotensin-converting enzyme (ACE) inhibitory activity was measured by a colorimetric method., Results: Three free bioactive peptides (LVVYPW, LVVYPWTQ and VVYPWTQ) were solely found in fermented DVA, the latter two of which are known ACE inhibitors. However matches to multiple ACE inhibitor cryptides were obtained within protein and peptide sequences of both unfermented and fermented DVA. In vitro analysis showed that the ACE inhibitory activity of DVA was more pronounced in the fermented sample, but both unfermented and fermented DVA had similar activity following release of cryptides by simulated gastrointestinal digestion., Conclusions: DVA contains multiple ACE inhibitory peptide sequences that may be released by fermentation or following oral consumption, and which may provide a health benefit through positive effects on the cardiovascular system. The study illustrates the power of in silico combined with in vitro methods for analysis of the effects of processing on bioactive peptides in complex functional ingredients like DVA.

Type 2 diabetes mellitus is a major health concern worldwide; however, the molecular mechanism underlying its development is poorly understood. The hormone amylin is postulated to be involved, as human amylin forms amyloid in the pancreases of diabetic patients, and oligomers have been shown to be cytotoxic to β-cells. As rodent amylin is non-amyloidogenic, mice expressing human amylin have been developed to investigate this hypothesis. However, it is not possible to differentiate the effects of amylin overexpression from β-cell loss in these models. We have developed transgenic mice that overexpress [ 25, 28, 29 triprolyl]human amylin, a non-amyloidogenic variant of amylin, designated the Line 44 model. This model allows us to investigate the effects of chronic overexpression of non-cytotoxic amylin. We characterised this model and found it developed obesity, hyperglycaemia and hyperinsulinaemia. This phenotype was associated with alterations in the expression of genes involved in the amylin, insulin and leptin signalling pathways within the brain. This included genes such as c-Fos (a marker of amylin activation); Socs3 (a leptin inhibitor); and Cart, Pomc and Npy (neuropeptides that control appetite). We also examined Socs3 protein expression and phosphorylated Stat3 to determine if changes at the mRNA level would be reflected at the protein level.

Se is an essential micronutrient for human health, and fluctuations in Se levels and the potential cellular dysfunction associated with it may increase the risk for disease. Although Se has been shown to influence several biological pathways important in health, little is known about the effect of Se on the expression of microRNA (miRNA) molecules regulating these pathways. To explore the potential role of Se-sensitive miRNA in regulating pathways linked with colon cancer, we profiled the expression of 800 miRNA in the CaCo-2 human adenocarcinoma cell line in response to a low-Se (72 h at <40 nm) environment using nCounter direct quantification. These data were then examined using a range of in silico databases to identify experimentally validated miRNA-mRNA interactions and the biological pathways involved. We identified ten Se-sensitive miRNA (hsa-miR-93-5p, hsa-miR-106a-5p, hsa-miR-205-5p, hsa-miR-200c-3p, hsa-miR-99b-5p, hsa-miR-302d-3p, hsa-miR-373-3p, hsa-miR-483-3p, hsa-miR-512-5p and hsa-miR-4454), which regulate 3588 mRNA in key pathways such as the cell cycle, the cellular response to stress, and the canonical Wnt/β-catenin, p53 and ERK/MAPK signalling pathways. Our data show that the effects of low Se on biological pathways may, in part, be due to these ten Se-sensitive miRNA. Dysregulation of the cell cycle and of the stress response pathways due to low Se may influence key genes involved in carcinogenesis.

Free-floating plants, like most groups of aquatic primary producers, can become nuisance vegetation under certain conditions. On the other hand, there is substantial optimism for the applied uses of free-floating plants, such as wastewater treatment, biofuel production, and aquaculture. Therefore, understanding the species-specific responses of floating plants to abiotic conditions will inform both management decisions and the beneficial applications of these plants. I measured the responses of three floating plant species common in the northeast United States (Lemna minor, Spirodela polyrhiza, and Wolffia brasiliensis) to nutrient stoichiometry (nitrogen and phosphorus) and temperature in the laboratory. I also used survey data to determine the pattern of species richness of floating plants in the field and its relationship with the dominance of this group. Floating plant species exhibited unique responses to nutrient stoichiometry and temperature in the laboratory, especially under low temperatures (18 °C) and low nutrient conditions (0.5 mg N L(-1), 0.083 mg P L(-1)). The three species displayed an apparent tradeoff with different strategies of growth or dormancy. In the field, water bodies with three or more species of floating plants were not more frequently dominated by this group. The response diversity observed in the lab may not be associated with the dominance of this group in the field because it is masked by environmental variability, has a weak effect, or is only important during transient circumstances. Future research to develop applied uses of floating plants should examine response diversity across a greater range of species or clones and environmental conditions.

A combination of local and regional factors and stochastic forces is expected to determine the occurrence of species and the structure of communities. However, in most cases, our understanding is incomplete, with large amounts of unexplained variation. Using functional groups rather than individual species may help explain the relationship between community composition and conditions. In this study, I used survey data from freshwater lakes and ponds to understand factors that determine the presence of the floating plant functional group in the northeast United States. Of the 176 water bodies surveyed, 104 (59.1%) did not contain any floating plant species. The occurrence of this functional group was largely determined by local abiotic conditions, which were spatially autocorrelated across the region. A model predicting the presence of the floating plant functional group performed similarly to the best species-specific models. Using a permutation test, I also found that the observed prevalence of floating plants is no different than expected by random assembly from a species pool of its size. These results suggest that the size of the species pool interacts with local conditions in determining the presence of a functional group. Nevertheless, a large amount of unexplained variation remains, attributable to either stochastic species occurrence or incomplete predictive models. The simple permutation approach in this study can be extended to test alternative models of community assembly.

Food quality and quantity, as well as temperature, are all factors that are expected to affect rates of development, and are likely to be affected by expected climatic change. We tested the effect of a mixed diet versus a single-food diet on metamorphic competence in the emerging model species Crepidula fornicata. We then compared our results with other published studies on this species that examined time to metamorphic competence across a range of food concentrations and rearing temperatures. Ours was the only study to test the effects of single food versus a mixed diet on metamorphic competence for this species. Diet composition did not affect metamorphic competence or survivorship. Comparing results across studies, we found that the shortest time to metamorphic competence was typically found when the food availability per larva was the greatest, independent of rearing temperature. Unfortunately, some published studies did not include important metadata needed for comparison with other studies; these data included larval rearing density, food density, frequency of feeding, and rearing temperature. Mortality rates were not always reported and when reported were often measured in different ways, preventing comparison. Such metadata are essential for comparisons among studies as well as among taxa, and for the determination of generalizable patterns and evolutionary trends. Increased reporting of all such metadata is essential if we are to use scientific studies performed to their fullest potential., (© 2014 Marine Biological Laboratory.)

The mammalian lignan, enterolactone, has been shown to reduce the proliferation of the earlier stages of prostate cancer at physiological concentrations in vitro. However, efficacy in the later stages of the disease occurs at concentrations difficult to achieve through dietary modification. We have therefore investigated what concentration(s) of enterolactone can restrict proliferation in multiple stages of prostate cancer using an in vitro model system of prostate disease. We determined that enterolactone at 20 μM significantly restricted the proliferation of mid and late stage models of prostate disease. These effects were strongly associated with changes in the expression of the DNA licencing genes (GMNN, CDT1, MCM2 and 7), in reduced expression of the miR-106b cluster (miR-106b, miR-93, and miR-25), and in increased expression of the PTEN tumour suppressor gene. We have shown anti-proliferative effects of enterolactone in earlier stages of prostate disease than previously reported and that these effects are mediated, in part, by microRNA-mediated regulation.

Inflammatory bowel disease (IBD) is a chronic relapsing disease. Genetic predisposition to the disease reduces an individual's capacity to respond appropriately to environmental challenges in the intestine leading to inappropriate inflammation. IBD patients often modify their diet to mitigate or reduce the severity of inflammation. Turmeric (Curcuma longa L., Zingiberaceae) has historically been used in Chinese, Hindu, and Ayurvedic medicine over several centuries to treat inflammatory disorders. To understand how turmeric may influence the consequences of a genetic predisposition to inappropriate inflammation, we used HEK293 cells to examine the in vitro capacity of turmeric extract and fractions to affect the functionality of two gene variants, solute carrier protein 22 A4 (SLC22A4, rs1050152) and interleukin-10 (IL-10, rs1800896) associated with IBD. We found that a turmeric extract and several chromatographically separated fractions beneficially affected the variants of SLC22A4 and IL-10 associated with IBD, by reducing inappropriate epithelial cell transport (SLC22A4, 503F) and increasing anti-inflammatory cytokine gene promoter activity (IL-10, -1082A). The effect of turmeric on the IL-10 variant was strongly associated with the curcumin content of the extract and its fractions.

The decreased cancer risk associated with consumption of olive oil may be due to the presence of phenolics which can modulate pathways including apoptosis and invasion that are relevant to carcinogenesis. We have previously shown that a virgin olive oil phenolics extract (OVP) inhibited invasion of HT115 colon cancer cells in vitro. In the current study we assessed the in vitro effects of OVP (25 μg mL(-1)) on HT115 cell migration, spreading and integrin expression. Furthermore, the anti-metastatic activity of OVP - at a dose equivalent to 25 mg per kg per day for 2, 8 or 10 weeks - was assessed in a Severe Combined ImmunoDeficiency (SCID) Balb-c mouse model. After 24 h OVP did not inhibit cell migration but significantly reduced cell spreading on fibronectin (65% of control; p < 0.05) and expression of a range of α and β integrins was modulated. In vivo, OVP by gavage significantly (p < 0.05) decreased not only tumour volume but also the number of metastases in SCID Balb-c mice. Collectively, the data suggest that - possibly through modulation of integrin expression - OVP decreases invasion in vitro and also inhibits metastasis in vivo.

Lactobacillus fermentum is found in fermented foods and thought to be harmless. In vivo and clinical studies indicate that some L. fermentum strains have beneficial properties, particularly for gastrointestinal health. However, L. fermentum AGR1487 decreases trans-epithelial electrical resistance (TEER), a measure of intestinal barrier integrity. The hypothesis was that L. fermentum AGR1487 decreases the expression of intestinal cell tight junction genes and proteins, thereby reducing barrier integrity. Transcriptomic and proteomic analyses of Caco-2 cells (model of human intestinal epithelial cells) treated with L. fermentum AGR1487 were used to obtain a global view of the effect of the bacterium on intestinal epithelial cells. Specific functional characteristics by which L. fermentum AGR1487 reduces intestinal barrier integrity were examined using confocal microscopy, cell cycle progression and adherence bioassays. The effects of TEER-enhancing L. fermentum AGR1485 were investigated for comparison. L. fermentum AGR1487 did not alter the expression of Caco-2 cell tight junction genes (compared to L. fermentum AGR1485) and tight junction proteins were not able to be detected. However, L. fermentum AGR1487 increased the expression levels of seven tubulin genes and the abundance of three microtubule-associated proteins, which have been linked to tight junction disassembly. Additionally, Caco-2 cells treated with L. fermentum AGR1487 did not have defined and uniform borders of zona occludens 2 around each cell, unlike control or AGR1485 treated cells. L. fermentum AGR1487 cells were required for the negative effect on barrier integrity (bacterial supernatant did not cause a decrease in TEER), suggesting that a physical interaction may be necessary. Increased adherence of L. fermentum AGR1487 to Caco-2 cells (compared to L. fermentum AGR1485) was likely to facilitate this cell-to-cell interaction. These findings illustrate that bacterial strains of the same species can cause contrasting host responses and suggest that food-safe status should be given to individual strains not species.

Scope: There is evidence that a mammalian lignan, enterolactone (ENL), decreases the proliferation rate of prostate cancer cells, although previous studies have used concentrations difficult to achieve through dietary modification. We have therefore investigated the anti-proliferative effects of ENL in an in vitro model of prostate tumourigenesis at concentrations reported to occur in a range of male populations., Methods and Results: The effects of 0.1 and 1 μM ENL on three markers of viability and proliferation (metabolic activity, growth kinetics, and cell cycle progression) were assessed in the RWPE-1, WPE1-NA22, WPE1-NB14, WPE1-NB11, WPE1-NB26, LNCaP, and PC-3 cell lines over 72 h. Based on these data, we quantified the expression levels of 12 genes involved in the control of DNA replication initiation using TaqMan real-time PCR in the WPE1-NA22, WPE1-NB14, WPE1-NB11, and WPE1-NB26 cell lines. ENL significantly inhibited the abnormal proliferation of the WPE1-NB14 and WPE1-NB11 cell lines and appears to be a consequence of decreased expression of abnormal chromatin licensing and DNA replication factor 1., Conclusion: In contrast to previous studies, concentrations of ENL that are reported after dietary intervention restrict the proliferation of early-stage tumourigenic prostate cell lines by inhibiting the abnormal formation of complexes that initiate DNA replication., (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The ability to predictably engineer the composition of bowel microbial communities (microbiota) using dietary components is important because of the reported associations of altered microbiota composition with medical conditions. In a synecological study, weanling conventional Sprague-Dawley rats (21 days old) were fed a basal diet (BD) or a diet supplemented with resistant starch (RS) at 5%, 2.5%, or 1.25% for 28 days. Pyrosequencing of 16S rRNA genes and temporal temperature gradient electrophoresis (TTGE) profiles in the colonic digesta showed that rats fed RS had altered microbiota compositions due to blooms of Bacteroidetes and Actinobacteria. The altered microbiota was associated with changes in colonic short-chain fatty acid (SCFA) concentrations, colonic-tissue gene expression (Gsta2 and Ela1), and host physiology (serum metabolite profiles and colonic goblet cell numbers). Comparisons between germ-free and conventional rats showed that transcriptional and serum metabolite differences were mediated by the microbiota and were not the direct result of diet composition. Altered transcriptomic and physiological responses may reflect the young host's attempts to maintain homeostasis as a consequence of exposure to a new collection of bacteria and their associated biochemistry.

The soybean-derived protease inhibitor, Bowman-Birk inhibitor (BBI), is currently showing great promise as a novel cancer chemopreventive agent. In contrast to the wealth of research conducted on this compound, the anticancer effects of protease inhibitors isolated from other leguminous sources have received limited attention. In the current study, 7 protease inhibitor concentrates (PICs) were isolated from various leguminous sources (including soybean) and characterized. The effects of PICs on the proliferation of breast and prostate cancer cells were investigated in vitro. Chickpea PIC significantly inhibited the viability of MDA-MB-231 breast cancer and PC-3 and LNCaP prostate cancer cells at all concentrations tested (25-400 μg/ml). In addition, kidney bean (200, 400 μg/ml), soybean (50, 100 μg/ml), and mungbean (100, 200 μg/ml) PICs inhibited LNCaP cell viability. These findings suggest that leguminous PICs may possess similar anticancer properties to that of soybean BBI and deserve further study as possible chemopreventive agents.

Background: Intestinal barrier function is important for preserving health, as a compromised barrier allows antigen entry and can induce inflammatory diseases. Probiotic bacteria can play a role in enhancing intestinal barrier function; however, the mechanisms are not fully understood. Existing studies have focused on the ability of probiotics to prevent alterations to tight junctions in disease models, and have been restricted to a few tight junction bridging proteins. No studies have previously investigated the effect of probiotic bacteria on healthy intestinal epithelial cell genes involved in the whole tight junction signalling pathway, including those encoding for bridging, plaque and dual location tight junction proteins. Alteration of tight junction signalling in healthy humans is a potential mechanism that could lead to the strengthening of the intestinal barrier, resulting in limiting the ability of antigens to enter the body and potentially triggering undesirable immune responses., Results: The effect of Lactobacillus plantarum MB452 on tight junction integrity was determined by measuring trans-epithelial electrical resistance (TEER) across Caco-2 cell layers. L. plantarum MB452 caused a dose-dependent TEER increase across Caco-2 cell monolayers compared to control medium. Gene expression was compared in Caco-2 cells untreated or treated with L. plantarum MB452 for 10 hours. Caco-2 cell RNA was hybridised to human oligonucleotide arrays. Data was analysed using linear models and differently expressed genes were examined using pathway analysis tools. Nineteen tight junction-related genes had altered expression levels in response to L. plantarum MB452 (modified-P < 0.05, fold-change > 1.2), including those encoding occludin and its associated plaque proteins that anchor it to the cytoskeleton. L. plantarum MB452 also caused changes in tubulin and proteasome gene expression levels which may be linked to intestinal barrier function. Caco-2 tight junctions were visualised by fluorescent microscopy of immuno-stained occludin, zona occludens (ZO)-1, ZO-2 and cingulin. Caco-2 cells treated with L. plantarum MB452 had higher intensity fluorescence of each of the four tight junction proteins compared to untreated controls., Conclusions: This research indicates that enhancing the expression of genes involved in tight junction signalling is a possible mechanism by which L. plantarum MB452 improves intestinal barrier function.

Ecological data suggest a long-term diet high in plant material rich in biologically active compounds, such as the lignans, can significantly influence the development of prostate cancer over the lifetime of an individual. The capacity of a pure mammalian lignan, enterolactone (ENL), to influence the proliferation of the LNCaP human prostate cancer cell line was investigated as a function of cell density, metabolic activity, expression and secretion of prostate specific antigen (PSA), cell cycle profile, and the expression of genes involved in development and progression of prostate cancer. Treatment with a subcytotoxic concentration of ENL (60 muM for 72 h) was found to reduce: cell density (57.5%, SD 7.23, p < 0.001), metabolic activity (55%, SD 0.03, p < 0.001), secretion of PSA (48.50% SD 4.74, p = 0.05) and induce apoptosis (8.33-fold SD 0.04, p = 0.001) compared to untreated cells. Cotreatment with 10 muM etoposide was found to increase apoptosis by 50.17% (SD 0.02, p < 0.001). Additionally, several key genes (e. g. MCMs, survivin and CDKs) were beneficially regulated by ENL treatment (p < 0.05). The data suggest that the antiproliferative activity of ENL is a consequence of altered expression of cell cycle associated genes and provides novel molecular evidence for the antiproliferative properties of a pure lignan in prostate cancer.

This study examined correlates of methamphetamine (MA) and marijuana (MJ) use and treatment response among treatment-involved youth (N = 4,430) in Los Angeles County, California treated between 2000 and 2005. Of the sample, 912 (21%) were primary MA and 3,518 (79%) were primary MJ users. Correlates of increased MA use included being female, White, Asian or Latino, older age, previous treatment involvement, legal status of probation or parole, and initiating drug use at an older age. Treatment trends showed a rise in treatment admissions for MA, with more MA users enrolling in residential treatment compared to outpatient treatment. Predictors of retention, drug use at discharge, and completion by treatment modality are discussed. Results can guide the development of effective strategies for treatment assessment and planning tailored towards minimizing drug use and maximizing treatment response among youth.

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.

Background: There is a probable association between consumption of fruit and vegetables and reduced risk of cancer, particularly cancer of the digestive tract. This anti-cancer activity has been attributed in part to anti-oxidants present in these foods. Raspberries in particular are a rich source of the anti-oxidant compounds, such as polyphenols, anthocyanins and ellagitannins., Methods: A "colon-available" raspberry extract (CARE) was prepared that contained phytochemicals surviving a digestion procedure that mimicked the physiochemical conditions of the upper gastrointestinal tract. The polyphenolic-rich extract was assessed for anti-cancer properties in a series of in vitro systems that model important stages of colon carcinogenesis, initiation, promotion and invasion., Results: The phytochemical composition of CARE was monitored using liquid chromatography mass spectrometry. The colon-available raspberry extract was reduced in anthocyanins and ellagitannins compared to the original raspberry juice but enriched in other polyphenols and polyphenol breakdown products that were more stable to gastrointestinal digestion. Initiation--CARE caused significant protective effects against DNA damage induced by hydrogen peroxide in HT29 colon cancer cells measured using single cell microgelelectrophoresis. Promotion--CARE significantly decreased the population of HT29 cells in the G1 phase of the cell cycle, effectively reducing the number of cells entering the cell cycle. However, CARE had no effect on epithelial integrity (barrier function) assessed by recording the trans-epithelial resistance (TER) of CACO-2 cell monolayers. Invasion--CARE caused significant inhibition of HT115 colon cancer cell invasion using the matrigel invasion assay., Conclusion: The results indicate that raspberry phytochemicals likely to reach the colon are capable of inhibiting several important stages in colon carcinogenesis in vitro.

The Center for Substance Abuse Treatment funded the Metamphetamine Treatment Project to evaluate and compare treatment approaches for methamphetamine users. As part of this study, drug use patterns, history of physical or sexual abuse, history of suicidality, and psychopathology were assessed in 1,016 methamphetamine-dependent outpatients entering treatment between 1999 and 2001 at eight sites across the western United States. The sample was predominately female and racially diverse. The mean age of the participants was 32.8 years. Most were methamphetamine smokers, but there were marked regional variations. Suicidality and physical or sexual abuse were common and measures of current psychopathology were high. These clinical issues were associated with more frequent use of methamphetamine and, more strongly, with concurrent use of other drugs. Therefore, the relationship between polydrug use and psychopathology in methamphetamine users warrants further investigation.

Aims: Previous research has reported that both contingency management (CM) and cognitive-behavioral therapy (CBT) are efficacious interventions for the treatment of stimulant abusers. The present study sought to directly compare the effectiveness of (CM) and (CBT) alone and in combination in reducing stimulant use., Design: Randomized clinical trial., Participants: Stimulant-dependent individuals (n = 171)., Intervention: CM, CBT or combined CM and CBT, 16-week treatment conditions. CM condition participants received vouchers for stimulant-free urine samples. CBT condition participants attended three 90-minute group sessions each week., Measurements: Participants were interviewed at baseline and weeks 17, 26 and 52. Measures included psychiatric disorders and alcohol and drug use and concomitant social problems., Findings: CM procedures produced better retention and lower rates of stimulant use during the study period. Self-reported stimulant use was reduced from baseline levels at all follow-up points for all groups and urinalysis data did not differ between groups at follow-up. While CM produced robust evidence of efficacy during treatment application, CBT produced comparable longer-term outcomes. There was no evidence of an additive effect when the two treatments were combined., Conclusions: This study suggests that CM is an efficacious treatment for reducing stimulant use and is superior during treatment to a CBT approach. CM is useful in engaging substance abusers, retaining them in treatment and helping them achieve abstinence from stimulant use. CBT also reduces drug use from baseline levels and produces comparable outcomes on all measures at follow-up.

This study examined participant characteristics and treatment response among substance-abusing adolescents who received outpatient treatment (N=305, 70.2% adolescent male, 55.3% White, 33.1% Latino, average age of 16 years). Chart reviews were performed on existing intake and discharge assessments between 1999 and 2003 from two Matrix Institute on Addictions treatment clinics. Analyses comparing methamphetamine (meth)-using (n=90) and non-meth-using (n=215) adolescents revealed that adolescent females and older youth were more likely to use meth. Meth users reported greater psychosocial dysfunction and higher rates of substance use at treatment discharge compared with non-meth users. Suicidal ideation and substance use during treatment were predictors of early treatment dropout among the total sample. Meth-using adolescents may need enhanced treatment programming, because they appear to present for treatment with higher levels of dysfunction. Implications are discussed in terms of developing strategies that minimize drug use and maximize treatment response among substance-abusing adolescents.

Prostate cancer is poised to become the most prevalent male cancer in the Western world. In Japan and China, incidence rates are almost 10-fold less those reported in the United States and the European Union. Epidemiological data suggest that environmental factors such as diet can significantly influence the incidence and mortality of prostate cancer. The differences in lifestyle between East and West are one of the major risk factors for developing prostate cancer. Traditional Japanese and Chinese diets are rich in foods containing phytoestrogenic compounds, whereas the Western diet is a poor source of these phytochemicals. The lignan phytoestrogens are the most widely occurring of these compounds. In vitro and in vivo reports in the literature indicate that lignans have the capacity to affect the pathogenesis of prostate cancer. However, their precise mechanism of action in prostate carcinogenesis remains unclear. This article outlines the possible role of lignans in prostate cancer by reviewing the current in vitro and in vivo evidence for their anticancer activities. The intriguing concept that lignans may play a role in the prevention and treatment of prostate cancer over the lifetime of an individual is discussed.

Aims: The Center for Substance Abuse Treatment (CSAT) Methamphetamine Treatment Project (MTP) is the largest randomized clinical trial of treatments for methamphetamine (MA) dependence to date. The objective of the study was to compare the Matrix Model, a manualized treatment method, with treatment-as-usual (TAU) in eight community out-patient settings in the Western United States., Design: Over an 18-month period between 1999 and 2001, 978 treatment-seeking, MA-dependent people were randomly assigned to receive either TAU at each site or a manualized 16-week treatment (Matrix Model)., Setting: The study was conducted as an eight-site out-patient trial, with six sites located in California and one each in Montana and Hawaii., Findings: In the overall sample, and in the majority of sites, those who were assigned to Matrix treatment attended more clinical sessions, stayed in treatment longer, provided more MA-free urine samples during the treatment period and had longer periods of MA abstinence than those assigned to receive TAU. Measures of drug use and functioning collected at treatment discharge and 6 months post-admission indicate significant improvement by participants in all sites and conditions when compared to baseline levels, but the superiority of the Matrix approach did not persist at these two timepoints., Conclusions: Study results demonstrate a significant initial step in documenting the efficacy of the Matrix approach. Although the superiority of the Matrix approach over TAU was not maintained at the post-treatment timepoints, the in-treatment benefit is an important demonstration of empirical support for this psychosocial treatment approach.

The Drug Addiction Treatment Act of 2000 allows qualifying physicians to prescribe buprenorphine out of office-based practices to treat opioid-dependent patients, with the requirement that they have the ability to refer them to ancillary counseling services. It is likely that these patients will be seen by a wide range of counselors with varying experience in treating addictions. In order to enable the spectrum of counselors working with buprenorphine patients to receive information regarding opioids, buprenorphine, opioid dependency, and relevant counseling approaches, an online course has been developed. The information and rationale provided in this course is summarized in this article, including: background information regarding opioids and buprenorphine; general issues in counseling patients with substance abuse disorders; and approaches to counseling buprenorphine patients.

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.

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 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.

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.

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.

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.

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.

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 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 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.

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.

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.

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.

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.

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.

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.

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.