Assessment of isocenter alignment during CT colonography: Implications for clinical practice.

INTRODUCTION: Optimization of image quality and patient radiation dose is achieved in part by positioning the patient at the isocenter of the CT gantry. The aim of this study was to establish whether there was increased isocenter misalignment (IM) in CT colonography (CTC) scans by comparing patient position during the prone part of a CTC to patient position during renal stone protocol CT (CT-KUB) and patient position during the supine part of a CTC to patient position during abdominopelvic CT (CT-AP). METHODS: Two hundred and twenty two consecutive outpatient adult CTC studies performed between January and December 2016 were retrospectively analyzed. Automated dose-tracking software was used to quantify IM in the x and y planes. Renal stone CT-KUB (n = 100) and standard CT-AP (n = 100) were used as comparison studies. RESULTS: IM during CTC was significantly greater in the y-axis compared with the x-axis for both prone (p = 0.002) and supine (p < 0.001) scanning. IM was significantly greater during prone CTC compared with CT-KUB (p = 0.008) and during supine CTC compared with CT-AP (p = 0.0001). IM was shown to be slightly greater in studies performed by more experienced radiographers (p = 0.04). IM was not associated with patient age, gender or size (p > 0.05 for all). CONCLUSION: Isocenter misalignment is greater during CT colonography compared with CT-KUB or CT-AP. Strategies for improving patient positioning could include radiographer education and automated patient centering solutions.

Inhibition of transforming growth factor-ß-activated kinase-1 blocks cancer cell adhesion, invasion, and metastasis.

BACKGROUND: Tumour cell metastasis involves cell adhesion and invasion, processes that depend on signal transduction, which can be influenced by the tumour microenvironment. N-6 polyunsaturated fatty acids, found both in the diet and in response to inflammatory responses, are important components of this microenvironment. METHODS: We used short hairpin RNA (shRNA) knockdown of TGF-ß-activated kinase-1 (TAK1) in human tumour cells to examine its involvement in fatty acid-stimulated cell adhesion and invasion in vitro. An in vivo model of metastasis was developed in which cells, stably expressing firefly luciferase and either a control shRNA or a TAK1-specific shRNA, were injected into the mammary fat pads of mice fed diets, rich in n-6 polyunsaturated fatty acids. Tumour growth and spontaneous metastasis were monitored with in vivo and in situ imaging of bioluminescence. RESULTS: Arachidonic acid activated TAK1 and downstream kinases in MDA-MB-435 breast cancer cells and led to increased adhesion and invasion. Knockdown of TAK1 blocked this activation and inhibited both cell adhesion and invasion in vitro. Tumour growth at the site of injection was not affected by TAK1 knockdown, but both the incidence and extent of metastasis to the lung were significantly reduced in mice injected with TAK1 knockdown cells compared with mice carrying control tumour cells. CONCLUSION: These data demonstrate the importance of TAK1 signalling in tumour metastasis in vivo and suggest an opportunity for antimetastatic therapies.

PI3K/Akt signalling is required for the attachment and spreading, and growth in vivo of metastatic scirrhous gastric carcinoma.

BACKGROUND: PI3K/Akt (PKB) pathway has been shown in several cell types to be activated by ligands to cell surface integrins, leading to the metastasis of tumour cells. The signalling pathways involved in the metastatic spread of human scirrhous gastric carcinoma cells have not been defined. METHODS: The role of the PI3K/Akt pathway in an extensive peritoneal-seeding cell line, OCUM-2MD3 and a parental cell line, OCUM-2M, was investigated by assessing in vitro adhesion and spreading assay, and in vivo peritoneal metastatic model. We also examined the correlation of PI3K/Akt pathway with integrin signals by immunoprecipitations, using cells by transfection with mutant p85 (Δp85). RESULTS: Adhesiveness and spreading of OCUM-2MD3 cells on collagen type IV was significantly decreased by PI3K inhibitors and expression of mutant p85, but not by inhibitors of protein kinase C (PKC) or extracellular signal-regulated kinase (ERK). Immunoprecipitation studies indicated that the PI3K/Akt pathway was associated with integrin signalling through Src and vinculin. In an in vivo experimental metastasis model, p85 inhibition reduced peritoneal metastasis of OCUM-2MD3 cells. CONCLUSION: PI3K/Akt signalling may be required for integrin-dependent attachment and spreading of scirrhous gastric carcinoma cells, and would be translated into generating better strategies to optimise their use in cancer clinical trials.

Linoleic acid enhances angiogenesis through suppression of angiostatin induced by plasminogen activator inhibitor 1.

BACKGROUND: The intake of dietary fatty acids is highly correlated with the risk of various cancers. Linoleic acid (LA) is the most abundant polyunsaturated fat in the western diet, but the mechanism(s) by fatty acids such as LA modulate cancer cells is unclear. In this study, we examined the role of LA in various steps in gastric cancer progression. METHODS: The difference in gene expression between LA-treated and untreated OCUM-2MD3 gastric carcinoma cells was examined by mRNA differential display. The involvement of candidate genes was examined by oligo- and plasmid-mediated RNA interference. Biological functions of several of these genes were examined using in vitro assays for invasion, angiogenesis, apoptosis, cell viability, and matrix digestion. Angiogenesis in vivo was measured by CD-31 immunohistochemistry and microvessel density scoring. RESULTS: LA enhanced the plasminogen activator inhibitor 1 (PAI-1) mRNA and protein expression, which are controlled by PAI-1 mRNA-binding protein. LA-stimulated invasion depended on PAI-1. LA also enhanced angiogenesis by suppression of angiostatin, also through PAI-1. LA did not alter cell growth in culture, but increased dietary LA-enhanced tumour growth in an animal model. CONCLUSION: Our findings suggest that dietary LA impacts multiple steps in cancer invasion and angiogenesis, and that reducing LA in the diet may help slow cancer progression.

Elevated dietary linoleic acid increases gastric carcinoma cell invasion and metastasis in mice.

BACKGROUND: Dietary (n-6)-polyunsaturated fatty acids influence cancer development, but the mechanisms have not been well characterised in gastric carcinoma. METHODS: We used two in vivo models to investigate the effects of these common dietary components on tumour metastasis. In a model of experimental metastasis, immunocompromised mice were fed diets containing linoleic acid (LA) at 2% (LLA), 8% (HLA) or 12% (VHLA) by weight and inoculated intraperitoneally (i.p.) with human gastric carcinoma cells (OCUM-2MD3). To model spontaneous metastasis, OCUM-2MD3 tumours were grafted onto the stomach walls of mice fed with the different diets. In in vitro assays, we investigated invasion and ERK phosphorylation of OCUM-2MD3 cells in the presence or absence of LA. Finally, we tested whether a cyclooxygenase (COX) inhibitor, indomethacin, could block peritoneal metastasis in vivo. RESULTS: Both the HLA and VHLA groups showed increased incidence of tumour nodules (LA: 53%; HLA: 89%; VHLA: 100%; P<0.03); the VHLA group also displayed increased numbers of tumour nodules and higher total volume relative to LLA group in experimental metastasis model. Both liver invasion (78%) and metastasis to the peritoneal cavity (67%) were more frequent in VHLA group compared with the LLA group (22% and 11%, respectively; P<0.03) in spontaneous metastasis model. We also found that the invasive ability of these cells is greatly enhanced when exposed to LA in vitro. Linoleic acid also increased invasion of other scirrhous gastric carcinoma cells, OCUM-12, NUGC3 and MKN-45. Linoleic acid effect on OCUM-2MD3 cells seems to be dependent on phosphorylation of ERK. The data suggest that invasion and phosphorylation of ERK were dependent on COX. Indomethacin decreased the number of tumours and total tumour volume in both LLA and VHLA groups. Finally, COX-1, which is known to be an important enzyme in the generation of bioactive metabolites from dietary fatty acids, appears to be responsible for the increased metastatic behaviour of OCUM-2MD3 cells in the mouse model. CONCLUSION: Dietary LA stimulates invasion and peritoneal metastasis of gastric carcinoma cells through COX-catalysed metabolism and activation of ERK, steps that compose pathway potentially amenable to therapeutic intervention.

Psychosocial factors in functional gastrointestinal disorders: an evolving phenomenon.

The psychosocial aspect of functional gastrointestinal disorders have a long and complicated investigative history. Emerging from the 1930s when the observations of individual investigators and clinicians was the norm we have evolved in the last 25 years to an increasingly sophisticated era of scientific observation using standardized nosology, validated psychometric instruments and have made use of emerging technology such as brain imaging, barostat testing and other technologies. The application of the scientific method to help improve out understanding of the relationship of psychosocial factors as they relate to gastrointestinal illnesses is slowly but surely revolutionizing gastroenterology practice. It is the purpose of this paper to review the history of "Psychosomatic Gastroenterology" to review the dimensions of psychosocial factors as they relate to gastroenterology and to review the emerging technologies which are helping us to develop this knowledge. Finally we will attempt to speculate on where the field will be going in the future.

Cyclic vomiting syndrome in adults.

Cyclic vomiting syndrome (CVS) was initially described in children but can occur in all age groups. Cyclic vomiting syndrome is increasingly recognized in adults. However, the lack of awareness of CVS in adults has led to small numbers of diagnosed patients and a paucity of published data on the causes, diagnosis and management of CVS in adults. This article is a state-of-knowledge overview on CVS in adults and is intended to provide a framework for management and further investigations into CVS in adults.

Treatment of gastroparesis: a multidisciplinary clinical review.

This clinical review on the treatment of patients with gastroparesis is a consensus document developed by the American Motility Society Task Force on Gastroparesis. It is a multidisciplinary effort with input from gastroenterologists and other specialists who are involved in the care of patients with gastroparesis. To provide practical guidelines for treatment, this document covers results of published research studies in the literature and areas developed by consensus agreement where clinical research trials remain lacking in the field of gastroparesis.

Subtypes of anal incontinence associated with bowel dysfunction: clinical, physiologic, and psychosocial characterization.

BACKGROUND: We hypothesized that functional anal incontinence with no structural explanation comprises distinct pathophysiologic subgroups that could be identified on the basis of the predominant presenting bowel pattern. METHODS: Consecutive patients (n = 80) were prospectively grouped by bowel symptoms as 1) incontinence only, 2) incontinence + constipation, 3) incontinence + diarrhea, and 4) incontinence + alternating bowel symptoms. The Hopkins Bowel Symptom Questionnaire, the Symptom Checklist 90-R, and anorectal manometry were completed. RESULTS: Significant group differences were found between subcategories of incontinent patients on the basis of symptoms. Abdominal pain was more frequent in patients with altered bowel patterns. Patients with alternating symptoms reported the highest prevalence of abdominal pain, rectal pain, and bloating. Basal anal pressures were significantly higher in alternating patients (P = 0.03). Contractile pressures in the distal anal canal were diminished in the incontinent-only and diarrhea groups (P = 0.004). Constipated patients with incontinence exhibited elevated thresholds for the urge to defecate (P = 0.027). Dyssynergia was significantly more frequent in patients with incontinence and constipation or alternating bowel patterns. CONCLUSIONS: Distinct patterns of pelvic floor dysfunction were identified in patient subgroups with anal incontinence, based on the presence or absence of altered bowel patterns. Physiologic assessments suggested different pathophysiologic mechanisms among the subgroups. The evaluation of patients with fecal incontinence should consider altered bowel function.

Swainsonine stimulates bone marrow cell proliferation and differentiation in different strains of inbred mice.

The immunomodulatory alkaloid swainsonine (8alphabeta-indolizidine-1alpha,2alpha,8beta-triol) has potential for overcoming the bone marrow suppressive effects of cancer chemotherapeutic drugs and radiation. The effect of swainsonine on bone marrow cellularity was evaluated in four different strains (C57BL/6; C3H-HEN; Balb/C and DBA-2 mice) of inbred mice subjected to multiple doses of the alkaloid. Swainsonine treatment stimulated bone marrow cell proliferation in all strains of mice. Examination of the peripheral blood did not reveal any increase in total leukocyte count. In vitro assessment of total colony-forming unit (CFU) capacity of bone marrow cells showed a two- to eight-fold increase in swainsonine treated mice of different strains compared to their corresponding controls given sham injections of physiological saline. Swainsonine induced increase in CFU capacity of bone marrow cells should find clinical application in cancer treatment with chemotherapeutic agents and radiation.

Health-related quality of life among persons with irritable bowel syndrome: a systematic review.

AIM: To perform a systematic review of the literature with three objectives: (1) to compare the health related quality of life (HRQoL) of patients with irritable bowel syndrome with that of healthy controls; (2) to compare the HRQoL of irritable bowel syndrome patients to those with other diseases; and (3) to examine therapy-associated changes in HRQoL of irritable bowel syndrome patients. METHODS: Searches of all English and non-English articles from 1980 to 2001 were performed in Medline and Embase, and two investigators performed independent data abstraction. RESULTS: Seventeen articles met our selection criteria. 13 studies addressed objective no. 1; 11 showed a significant reduction in HRQoL among irritable bowel syndrome patients. Of these, only one study was considered of high quality. Four studies addressed objective no. 2, none of which was considered to be high quality in addressing this objective. Four trials (three of high quality) addressed objective no. 3. One showed that symptomatic improvement with Leupron compared to placebo was accompanied an improvement only in the comparative health domain of the HRQoL. The second study reported significant positive changes in HRQoL after 12 weeks of cognitive behavioural therapy. The third report of two placebo-controlled studies indicated significant improvement with alosetron on most domains of Irritable Bowel Syndrome Quality of Life Questionnaire. CONCLUSIONS: (i) There is reasonable evidence for a decrease in HRQoL in patients with moderate to severe irritable bowel syndrome; however, the data are conflicting regarding the impact of irritable bowel syndrome on HRQoL in population-based studies of nonconsulters. (ii) HRQoL in irritable bowel syndrome patients is impaired to a degree comparable to other chronic disorders such as GERD and depression. (iii) A therapeutic response in irritable bowel syndrome-related pain has a corresponding improvement in HRQoL. (iv) Limitations of the literature include focusing on moderate-severe irritable bowel syndrome in referral centres, and lack of appropriate controls

A bold new direction for environmental health research.

The biotechnology revolution has opened new opportunities for addressing current inadequacies in decision making regarding environmental health. Strategic investments need to be made (1) to develop high-throughput technologies that could accelerate toxicity testing and generate a mechanistic understanding of toxicity, (2) to incorporate individual susceptibility into risk assessments, and (3) to establish a rational basis for testing and regulatory decision making. New initiatives of the National Institute of Environmental Health Sciences, including the Environmental Genome Project and the Toxicogenomics Center, are discussed.

Cis-polyunsaturated fatty acids stimulate beta1 integrin-mediated adhesion of human breast carcinoma cells to type IV collagen by activating protein kinases C-epsilon and -mu.

We have investigated the effects of various fatty acids (FAs) on integrin-mediated MDA-MB-435 breast carcinoma cell adhesion to type IV collagen (collagen IV) in vitro. Arachidonic acid (AA) and linoleic acid both induced a dose-dependent increase in cell adhesion to collagen IV with no significant increase in nonspecific adhesion to polylysine and BSA. Oleic acid (a monounsaturated FA), AA methyl ester, and linoelaidic acid (a trans-isomer of linoleic acid) failed to stimulate adhesion to collagen IV, suggesting that these effects required cis-polyunsaturation and a free carboxylic moiety and that they were not due to membrane perturbations. Calphostin C, a protein kinase C (PKC) inhibitor, blocked cis-polyunsaturated FA (cis-PUFA)-induced cell adhesion in a dose-dependent manner, suggesting a role for a calcium-dependent PKC in this signal transduction pathway. Immunoblotting revealed that cis-PUFAs induced the translocation of PKCepsilon and PKCmu, two of the novel PKC isozymes, from the cytosol to the membrane. In contrast, a conventional PKC isozyme, PKCalpha, as well as the atypical isozymes, PKCzeta and PKCiota, did not translocate after cis-PUFA treatment. Function-blocking antibodies specific for alpha1, alpha2, and beta1, integrin subunits inhibited cell adhesion to collagen IV, whereas antibodies to alpha3 and alpha5 did not. No increase in the expression of these integrins on the cell surface was detected after the incubation of cells with cis-PUFAs, suggesting that there is an increase in the activity, but not in the amount, of these beta1, integrins. Altogether, these data suggest that cis-PUFAs enhance human breast cancer cell adhesion to collagen IV by selectively activating specific PKC isozymes, which leads to the activation of beta1 integrins.

Genomics: implications for toxicology.

The primary goal of the Environmental Genome Project (EGP) is the identification of human polymorphisms indicative of susceptibility to specific environmental agents. Despite evidence for a substantial genetic contribution to disease variation in the population, progress towards identifying specific genes has been slow. To date, most of the advances in our understanding of human diseases has come from genetic analyses of monogenic diseases that affect a relatively small portion of the population. The principal strategy of the EGP involves resequencing DNA samples from populations representative of the US racial and ethnic groups to develop a database of variations. Polymorphisms in specific genes may also be detected by gene-expression profiling. The identification of polymorphisms by resequencing is straightforward, and can be accomplished with minimal difficulty. Gene-expression profiling is still problematic; however, determining the functional significance of the allelic variations will be a monumental challenge involving sophisticated proteomics and population-based and animal model studies. These studies will change radically the practice of public health and clinical medicine, and the approach to the development of pharmaceuticals.

Irritable bowel syndrome. A survey of nurses' knowledge.

Nurses in a variety of clinical settings are often involved in educating and managing patients with irritable bowel syndrome, though their knowledge and perceptions of irritable bowel syndrome are not well known. A national survey was undertaken as a part of a larger study of patients and healthcare providers to determine nurses' knowledge of irritable bowel syndrome, including diagnosis, etiology, disease impact, management, beliefs, and attitudes regarding irritable bowel syndrome. In addition, the nurses' perceptions of the effect of irritable bowel syndrome on the patient's lifestyle and the severity of symptoms were compared to those of irritable bowel syndrome patients. One hundred practicing registered nurses were randomly selected and then interviewed by telephone using a questionnaire. A random-digit dialing method was used to identify and recruit 1,014 women with irritable bowel syndrome. The majority of registered nurses interviewed (75%) felt that nurses played a moderate-to-major role in counseling patients with irritable bowel syndrome. Only 13%, however, were aware of the diagnostic criteria for irritable bowel syndrome. The majority of nurse subjects felt the current therapies for irritable bowel syndrome had limited effectiveness varying from 6-21% depending on the symptom being treated. Almost half of the nurses felt they had an important role in management of irritable bowel syndrome and that both they and their patients needed more education about irritable bowel syndrome. There was close agreement between the nurses and the patients with regard to the impact of irritable bowel syndrome. With increased public attention on irritable bowel syndrome as a common problem affecting women, there is a need for nurses working in a variety of settings to have increased knowledge regarding the syndrome. In this article, recommendations are made regarding how to increase nurses' knowledge about this common health problem.

Psychologic and psychiatric aspects of gastrointestinal disease.

There has been an explosion in understanding of the psychosocial concomitants of functional gastrointestinal disorders. Detecting psychologic disturbance and eliciting a history of physical or sexual abuse are critical in suggesting comprehensive and efficacious treatment strategies for these patients. The challenge is to define further the use of psychopharmacologic agents, including the newer antidepressants, anticonvulsants, and anxiolytic agents, in the treatment of chronic functional gastrointestinal disorders. Further research to evaluate the usefulness of various forms of psychotherapeutic and behavioral interventions needs to be undertaken. Establishing a multicomponent treatment program delivered by a team of caregivers, each bringing their unique skills (internist, psychiatrist, psychologist, and others) to patients, must be based on further research on the efficacy of these modalities as opposed to empiric treatment.

Colonic perforation in unsuspected amebic colitis.

Unsuspected amebic colitis presenting as inflammatory bowel disease, as in our patient, has been previously reported (4, 7, 8). Misdiagnosis, delay in antibiotic treatment, and institution of immunosuppression were the result of failure to identify the parasite in stool specimens and have resulted in suffering, morbidity, mortality, and surgery. In all previously reported cases, routine stool studies failed to identify E. histolytica (4, 7, 8). The correct diagnosis was only established after reviewing the surgical specimen or biopsies obtained endoscopically. Because the erroneous diagnosis of inflammatory bowel disease can lead to disastrous complications, it is imperative to exclude amebic colitis prior to undertaking steroid therapy, especially in patients with a prior history of travel to or residence in areas with endemic E. histolytica (17). We recommend obtaining at least three stool specimens for microscopic examination, as well as testing for serum amebic antibody. Patients should submit fresh stool specimens directly to the laboratory to allow for prompt diagnostic evaluation. Such an approach might lead to the improved diagnosis of amebiasis.

Women's health and the environment in the 21st century.

For many years, the National Institute of Environmental Health Sciences has been a leader in studying the role of environmental factors in the causation of diseases that are particularly prevalent or unique to women. As we enter the next millennium, we face exciting new possibilities in broadening our understanding of how the environment impacts women's health. Sophisticated new technology and scientific information are now available to help us more precisely define environmental contributions to disease. Moreover, further development of our information base in environmental health sciences will usher in a new era of informed preventive care for women of all ages. The hallmark of this new era will be our ability to finally address the etiology and prevention of disease, rather than simply focusing on treatment and management of human illness.