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Background Carbon monoxide is a common environmental toxin, and some patients present with features of cardiac injury in addition to the noxious effects of carbon monoxide poisoning. A very small fraction of those have a transient left ventricular apical ballooning syndrome or Takotsubo cardiomyopathy, both terms are used to define a syndrome that affects the systolic function of the heart. It usually presents with elevated troponin levels with or without electrocardiographic changes. Cardiac angiograms generally illustrate coronary arteries without significant obstruction. Case Report Here we report the curious case of a 37-year-old Hispanic man brought in for carbon monoxide poisoning, but found to have significantly elevated troponin levels. Echocardiogram demonstrated decreased ejection fraction of 35%. Left heart catheterization 2 days after admission revealed patent coronary arteries, improved ejection fraction to 45%, and wall motion abnormalities plus apical ballooning compatible with Takotsubo cardiomyopathy. The case is unusual because our patient differs from the classically defined elderly, postmenopausal female demographic, and did not experience an emotional crisis that could have provoked this series of events. It is also noteworthy for the fact that the only identifiable trigger was exposure to carbon monoxide. Why Should an Emergency Physician Be Aware of This? Carbon monoxide poisoning is a common occurrence resulting in a multitude of annual emergency department visits. Given the known toxic effects of carbon monoxide poisoning on the heart, prompt cardiac workup is important to prevent overlooking a major, although rare, manifestation of carbon monoxide exposure.

Cephalopods fascinate us but have been out of the reach of experimental manipulations at the genetic level. A new study describes editing of a gene in a squid using CRISPR.

Though new or altered bodily sensations are a common occurrence they rarely transition to biomedically defined symptoms. When they do, sensations are subject to an appraisal process that can culminate in help-seeking. The transition has particular relevance for cancer diagnoses. Studies of 'symptom appraisal' in cancer patients typically conclude that failure to regard sensations as serious or 'symptom misattribution' results in lengthier help-seeking intervals. Though multiple influences on appraisal processes are acknowledged,including the socio-cultural context, detailed description and analyses of how socio-cultural fact ors shape appraisal is lacking. In this paper we explore one substantial component of the sociocultural context, namely, publicly recognised shared cancer narratives, and their impact on appraisal. We undertook a secondary analysis of 24 interviews with Scottish colorectal cancer patients originally completed in 2006-2007. Our analysis showed that fear, death and severity dominated cancer narrative s and were frequently restated throughout interviews. Yet, early bodily changes were often mild and vague, were commonly experienced in the context of 'feeling well' and failed to match preconceived ideas of what cancer 'feels like'. Moreover, few perceived themselves to be 'at risk' of cancer and diagnoses were characterised as 'shocking' events. Participants engaged in self-monitoring strategies and severe or painful changes prompted help-seeking. Far from misattributing symptoms, responses to bodily changes were sensible and measured; responses are particularly apt in relation to current policy rhetoric,which urges measured use of services. Our findings have resonance across healthcare settings as patients are required to negotiate a narrow and challenging space when making decisions to seek help. There is a pressing need for a more realistic approach to symptom appraisal in order to reduce help-seeking intervals. Future awareness campaigns should emphasise the importance of vague/minor bodily changes although this will necessitate discussions with health professionals on referral thresholds to achieve earlier detection.

Long noncoding RNAs (lncRNAs) have gained widespread attention as a new layer of regulation in biological processes during development and disease. The lncRNA ELDR (EGFR long noncoding downstream RNA) was recently shown to be highly expressed in oral cancers as compared to adjacent nontumor tissue, and we previously reported that ELDR may be an oncogene as inhibition of ELDR reduces tumor growth in oral cancer models. Furthermore, overexpression of ELDR induces proliferation and colony formation in normal oral keratinocytes (NOKs). In this study, we examined in further detail how ELDR drives the neoplastic transformation of normal keratinocytes. We performed RNA-seq analysis on NOKs stably expressing ELDR (NOK-ELDR), which revealed that ELDR enhances the expression of cell cycle-related genes. Expression of Aurora kinase A and its downstream targets Polo-like kinase 1, cell division cycle 25C, cyclin-dependent kinase 1, and cyclin B1 (CCNB1) are significantly increased in NOK-ELDR cells, suggesting induction of G2/M progression. We further identified CCCTC-binding factor (CTCF) as a binding partner of ELDR in NOK-ELDR cells. We show that ELDR stabilizes CTCF and increases its expression. Finally, we demonstrate the ELDR-CTCF axis upregulates transcription factor Forkhead box M1, which induces Aurora kinase A expression and downstream G2/M transition. These findings provide mechanistic insights into the role of the lncRNA ELDR as a potential driver of oral cancer during neoplastic transformation of normal keratinocytes.

Background The sural nerve (SN) is a cutaneous sensory nerve innervating the posterolateral leg. The SN is formed from a highly variable set of contributing nerves called the sural nerve complex (SNC). The SNC is made up of the lateral sural cutaneous nerve, medial sural cutaneous nerve, sural communicating branch, and SN. The SN is frequently cited as the most common donor nerve graft and is commonly injured in procedures of the lower extremity. Recent meta-analysis standardized six morphologies of the SNC and established a required reporting criterion for the group of nerves forming the SN. Due to the inconsistencies in previous literature, this study will group observed SNC's by one of these six SNC morphologies to assess and validate the meta-analysis grouping criteria. This study will also collect the same morphometric data previously outlined in order to grow the number of samples that are reported in a standardized fashion. Methods 100 formalin and 4 Theil preserved cadavers (n = 208) lower limbs were bilaterally dissected at Kansas City University and Creighton University School of Dentistry to observe the SNC in its entirety on the posterolateral leg. Anatomic data was captured utilizing the standardized morphologies types 1–6 with two sub-typing. Nerves that were found to be outside of this categorization were placed in an unassigned grouping. Results The most prevalent SNCs were type 1 at 41.35% (n = 86) and type 3 nerves at 34.62% (n = 72). Type 2 was found 8.65% (n = 18), type 4 and 5 were found each at 0.48% (n = 1). Type 6 was not observed. When comparing the present studies frequency of nerve types 1–6 to the meta-analysis a sub-grouping of “North American” cadaveric studies a X2 = .903 p = .030 was found. Two distinct and previously unassigned formations of the SNC were 10.58% (n = 20) and 3.85% (n = 8) of data. These two SNC are termed type 7 & 8, these represent two formations of SN that are outside of what was previously reported. 15.87% (n = 33) did not match visual descriptions based on nerve origin of a type 1 SNC but met written definitions. These were termed type 1A1 and type 1A2. The SNC was asymmetrical in 57.69% (n = 120). The pooled mean length of the SN was 32.97 ± 14.12 cm (31.05–34.88), mean diameter was 2.31 ± 0.83 mm (2.20–2.42, and the distance of the posterior border of the lateral malleolus to the SN was found to be 1.72 ± 0.70 cm (1.63–1.80). Conclusion Anatomic variation in the SNC is highly variable, yet is consistent with previously observed literature. This study demonstrates two unaccounted formations of the SNC as well as two additional subcategories of SNC that were not included in the previous meta-analysis. These four variants warrant inclusion as standard formations of the SNC due to the high prevalence observed in this study as well as historical consistency observed in previous literature and case reports. These two SNC formations increase the risk of iatrogenic injury during surgical interventions of the lower extremity. Morphometric data describing the spatial relationship of this nerve complex on the posterolateral leg is consistent with previously reported data and aids in generating a large data set for future studies to characterize spatial properties of this nerve complex.

Hydra, a simple freshwater animal famous for its regenerative capabilities, must tear a hole through its epithelial tissue each time it opens its mouth. The feeding response of Hydra has been well-characterized physiologically and is regarded as a classical model system for environmental chemical biology. However, due to a lack of in vivo labeling and imaging tools, the biomechanics of mouth opening have remained completely unexplored. We take advantage of the availability of transgenic Hydra lines to perform the first dynamical analysis, to our knowledge, of Hydra mouth opening and test existing hypotheses regarding the underlying cellular mechanisms. Through cell position and shape tracking, we show that mouth opening is accompanied by changes in cell shape, but not cellular rearrangements as previously suggested. Treatment with a muscle relaxant impairs mouth opening, supporting the hypothesis that mouth opening is an active process driven by radial contractile processes (myonemes) in the ectoderm. Furthermore, we find that all events exhibit the same relative rate of opening. Because one individual can open consecutively to different amounts, this suggests that the degree of mouth opening is controlled through neuronal signaling. Finally, from the opening dynamics and independent measurements of the elastic properties of the tissues, we estimate the forces exerted by the myonemes to be on the order of a few nanoNewtons. Our study provides the first dynamical framework, to our knowledge, for understanding the remarkable plasticity of the Hydra mouth and illustrates that Hydra is a powerful system for quantitative biomechanical studies of cell and tissue behaviors in vivo.

Hepatocellular carcinoma (HCC) is one of the most aggressive cancers and is the third leading cause of all cancer-related death. Limited noninvasive biomarkers are available for HCC detection. Early detection is the key in improving the survival of HCC patients. In this study, we tested the hypothesis that serum miRNAs can be used as a potential biomarker for HCC. Quantitative RT-PCR for miRNA analysis was performed using 70 serum samples. Receiver operating characteristic analysis was performed to measure the prognostic power of the miRNAs. The miRNA expression level was also measured from liver biopsy samples. Our study revealed that two miRNAs, miR-30e and miR-223, were expressed at significantly lower levels (P

Background: Quantitative faecal immunochemical tests (FIT) measure faecal haemoglobin concentration (f-Hb), which increases in the presence of colorectal neoplasia and is related to the severity of disease. We examined the diagnostic accuracy of FIT in patients at moderate to high risk of colorectal cancer (CRC) attending for surveillance colonoscopy as per national guidelines. Methods: We undertook a prospective study in two University hospitals, one in Scotland and one in England. Between June 2014 and September 2016, 1103 consecutive patients were invited to complete a FIT before their scheduled colonoscopy: f-Hb was analysed on an OC-Sensor io automated analyser (Eiken Chemical Co., Ltd, Tokyo, Japan)) with a limit of detection (LoD) of 2 µg Hb/g faeces. The diagnostic accuracy of f-Hb for CRC and higher-risk adenoma (HRA) was examined. Findings: 643 patients returned a FIT. Four patients with known IBD were excluded, leaving 639 (57·9%) in the study: age range: 25-90 years (median: 64 years, IQR: 55-71): 54·6% male. Of 593 patients who returned a FIT and completed colonoscopy, 41 (6·9%) had advanced neoplasia (4 CRC, 37 HRA): 238/593 patients (40·1%) had detectable f-Hb of whom 31 (13·0%) had advanced neoplasia (2 CRC, 29 HRA) compared to 10 (2·8%) in those with undetectable f-Hb (2 CRC, 8 HRA).Detectable f-Hb gave negative predictive values of 99·4% for CRC and 97·2% for CRC plus HRA. Interpretation: In patients at moderate to high risk of CRC who are under colonoscopy surveillance, a FIT at the LoD can provide an objective estimate of the risk of advanced neoplasia and could enable tailored scheduling of colonoscopy. Funding Statement: Chief Scientist Office; grant reference number CZH/4/1032. Declaration of Interests: CGF has undertaken consultancy with Kyowa-Medex Co., Ltd, Tokyo, Japan, and has received travel support from Alpha Labs Ltd, Eastleigh, UK. Other authors - none. Ethics Approval Statement: This study had ethical approval from NRES North of Scotland Ethics Committee: reference: 14/NS/0059.

Cnidarians (corals, anemones, jellyfish and hydras) are a diverse group of animals of interest to evolutionary biologists, ecologists and developmental biologists. With the publication of the genome sequences of Hydra and Nematostella, whose last common ancestor was the stem cnidarian, researchers are beginning to see the genomic underpinnings of cnidarian biology. Cnidarians are known for the remarkable plasticity of their morphology and life cycles. This plasticity is reflected in the Hydra and Nematostella genomes, which differ to an exceptional degree in size, base composition, transposable element content and gene conservation. It is now known what cnidarian genomes, given 500 million years, are capable of; as we discuss here, the next challenge is to understand how this genomic history has led to the striking diversity seen in this group.

Summary Background Local recurrence rates in operable rectal cancer are improved by radiotherapy (with or without chemotherapy) and surgical techniques such as total mesorectal excision. However, the contributions of surgery and radiotherapy to outcomes are unclear. We assessed the effect of the involvement of the circumferential resection margin and the plane of surgery achieved. Methods In this prospective study, the plane of surgery achieved and the involvement of the circumferential resection margin were assessed by local pathologists, using a standard pathological protocol in 1156 patients with operable rectal cancer from the CR07 and NCIC-CTG CO16 trial, which compared short-course (5 days) preoperative radiotherapy and selective postoperative chemoradiotherapy, between March, 1998, and August, 2005. All analyses were by intention to treat. This trial is registered, number ISRCTN 28785842. Findings 128 patients (11%) had involvement of the circumferential resection margin, and the plane of surgery achieved was classified as good (mesorectal) in 604 (52%), intermediate (intramesorectal) in 398 (34%), and poor (muscularis propria plane) in 154 (13%). We found that both a negative circumferential resection margin and a superior plane of surgery achieved were associated with low local recurrence rates. Hazard ratio (HR) was 0·32 (95% CI 0·16–0·63, p=0·0011) with 3-year local recurrence rates of 6% (5–8%) and 17% (10–26%) for patients who were negative and positive for circumferential resection margin, respectively. For plane of surgery achieved, HRs for mesorectal and intramesorectal groups compared with the muscularis propria group were 0·32 (0·16–0·64) and 0·48 (0·25–0·93), respectively. At 3 years, the estimated local recurrence rates were 4% (3–6%) for mesorectal, 7% (5–11%) for intramesorectal, and 13% (8–21%) for muscularis propria groups. The benefit of short-course preoperative radiotherapy did not differ in the three plane of surgery groups (p=0·30 for trend). Patients in the short-course preoperative radiotherapy group who had a resection in the mesorectal plane had a 3-year local recurrence rate of only 1%. Interpretation In rectal cancer, the plane of surgery achieved is an important prognostic factor for local recurrence. Short-course preoperative radiotherapy reduced the rate of local recurrence for all three plane of surgery groups, almost abolishing local recurrence in short-course preoperative radiotherapy patients who had a resection in the mesorectal plane. The plane of surgery achieved should therefore be assessed and reported routinely. Funding Medical Research Council (UK) and the National Cancer Institute of Canada.

Since the discovery of p53, a vast wealth of knowledge on its function and regulation has been accumulated. It is known that it is a key tumour suppressor and that its function is lost in many types of cancers, either by mutation or by excessive negative regulation. Recently, several discoveries have re-energised P53 as a therapeutic target as it has been shown that reintroduction of functional p53 into tumours has a therapeutic benefit. These encouraging results clearly justify the search for small molecules that diminish negative regulation of P53 in tumour cells, where P53 is not mutated as well as compounds that reactivate mutant P53. Important findings have been made to deal with both situations. Additionally, some of the small molecules identified may also help reduce the side effects of commonly used cancer therapeutics. These studies are still in their infancy and require further therapeutic validation, but the future appears bright for finally harnessing p53's tumour suppressing ability.

Screening for colorectal cancer by use of guaiac-based faecal occult blood tests (FOBT) reduces disease-specific mortality. However, due to imperfect specificity, about half of individuals positive for guaiac FOBT are negative for neoplasia on colonoscopy. We aimed to assess whether the testing of individuals positive for guaiac FOBT in a screening programme for colorectal cancer by use of a sensitive immunochemical FOBT could select more appropriately those who should receive colonoscopy.We invited individuals who were guaiac FOBT positive in the second screening round of a pilot study in Scotland, UK, to give two samples, each from separate stools, for immunochemical FOBT while awaiting colonoscopy. Results were classed as: both samples negative (N/N), one sample negative and one positive (N/P), and both samples positive (P/P); data were assessed for sampling bias. We compared immunochemical findings with those from colonoscopy using odds ratios of positive samples (P/P) versus negative (N/N and N/P). Sensitivity, specificity, and positive and negative likelihood ratios for cancer, and for cancer and high-risk adenomatous polyps were also calculated.1486 participants were invited and 801 (54%) sets of duplicate samples were returned. We found no evidence of sampling bias with regard to sex, age, or degree of positivity on guaiac FOBT. Of 800 sets returned with consent and analysed, 173 (22%) were N/N, 129 (16%) were N/P, and 498 (62%) were P/P. Chi2 test showed a highly significant positive correlation between degree of positivity on guaiac FOBT and on immunochemical FOBT (p0.003). 795 individuals had data for colonoscopy: one (1%) of 171 N/N participants and one (1%) of 127 N/P participants had colorectal cancer, compared with 38 (8%) of 497 P/P participants; adenomatous polyps were found in 28 (16%) N/N individuals, 24 (19%) N/P individuals, and 193 (39%) P/P individuals. Normal colonoscopy was less common in the P/P group (85 [17%]) than in the N/N (67 [39%]) and N/P (49 [39%]) groups. The odds ratio for P/P being associated with cancer was 7.57 (95% CI 1.84-31.4) and with high-risk adenomatous polyps was 3.11 (1.86-5.18). Sensitivity of a P/P result for cancer was 95.0% (81.8-99.1), and for cancer and high-risk adenomatous polyps was 90.1% (84.4-94.0); specificity was 39.5% (36.0-43.1) and 47.8% (43.9-51.8), respectively.Immunochemical FOBT for individuals with positive guaiac FOBT could decrease substantially the number of false positives in a screening programme for colorectal cancer.

Background: In recent years proteomic approaches have been widely used to diagnose disease and the new technology of surface enhanced laser-desorption and ionization time-of-flight mass spectrometry (SELDI-TOF MS) is very promising. Methods: A review of english language literature was undertaken using internet databases such as PubMed and Medline for studies using proteomic technologies for the early detection of cancer. Results: SELDI-TOF is an array based mass spectrometric method in which proteins of interest are selectively absorbed onto a chemically modified surface and the mass and amount of each protein is measured by irradiating the surface with a laser and measuring the time-of-flight. The technology has revealed a large number of previously uncharacterized biomarkers for a wide variety of cancers. Its versatility has also been demonstrated by its application as a tool for mining a wide variety of biological tissues and fluids. Conclusions: The majority of these studies have discriminated between diseased and healthy controls with a high degree of sensitivity and specif city. The reproducibility, standardization and feasibility of this technology need to be addressed before these proteomic approaches to the discovery of novel, highly sensitive diagnostic tools can become routine clinical care

The p53 tumour suppressor gene is thought to be central in protecting against the development of cancer, and this article reviews current understanding of its function and potential clinical significance. Information for this review was obtained from previous review articles, references cited in original papers, a Pubmed search of the last twelve months' literature and by scanning the latest issues of relevant journals. P53 can be described as a stress response gene, its product (the p53 protein) acting to induce apoptosis or cell-cycle arrest in response to DNA damage, thereby maintaining genetic stability in the organism. These functions are realised by a series of steps known as the "p53 pathway" involving induction of the expression of a number of other genes. As p53 is the most commonly mutated gene in human cancer, it has attracted a great deal of interest in the areas of prognosis, diagnosis and therapy, and p53 gene therapy is becoming established as a useful adjunct to conventional cancer treatment.

Prostate cancer is the most common and invasive type of cancer among American men, and the second leading cause of cancer-elated deaths in the United States. Unfortunately, an effective therapeutic regimen is still lacking for advance stages of the disease. Recently, MEK5 has been shown to overexpress in prostate cancer and is associated with poor survival outcome. MEK5 exists as alpha- and beta-isoforms. MEK5alpha induces cell proliferation by activating its downstream molecules, whereas MEK5beta expression is associated with inhibition of cell growth. We have recently shown that exogenous expression of c-myc promoter-binding protein 1 (MBP-1) induces prostate cancer cell death (Ghosh, A. K., Steele, R., and Ray, R. B. (2005) Cancer Res. 65, 718-721). In this study, we have investigated whether inhibition of MEK5 signaling pathway can modulate prostate cancer cell growth. MBP-1 is a general transcriptional repressor and modulates a number of cellular genes. Therefore, we examined the endogenous expression status of MEK5 in androgen-independent prostate cancer cells upon recombinant adenovirus-mediated introduction of MBP-1. Our results demonstrated that MBP-1 expression reduced the endogenous MEK5alpha protein level; on the other hand, MEK5beta expression was enhanced significantly. Transduction of MBP-1 modulates the downstream signaling molecules of MEK5, such as activation of the cyclin D1 promoter and MEF2C transcriptional activities in androgen-independent prostate cancer cells. MBP-1 expression also modulates MEK5-mediated activation of NF-kappaB. Further analysis suggested that MBP-1 physically associates with MEK5 and induces proteasome-mediated degradation of the MEK5 protein, which appears to occur independently of ubiquitination. Together, our results suggested a novel role of MBP-1 for suppression of prostate cancer cell growth by regulating the MEK5-mediated signaling pathway.

Hepatitis C virus (HCV) is a serious human pathogen and an estimated 170 million people are infected worldwide. Current therapeutic regimens have shown limited efficacy against selected genotypes of the virus. The phenomenon of RNA interference can be used to selectively block homologous genes post-transcriptionally, and has revolutionized approaches to study gene function. In this report, we have demonstrated that small interfering RNAs (siRNAs) targeted against NS5A of HCV genotype 1a specifically inhibit NS5A RNA and protein expression in a human hepatoma (HepG2) cell line. Expression of endogenous α-actin and the ds-RNA activated serine/threonine kinase-PKR were unaltered, demonstrating that the inhibitory effect observed from siRNA was specific to the HCV NS5A protein. We next examined whether siRNA directed against NS5A could inhibit core protein expression, the first gene product synthesized in virus infected cells due to its localization at the 5′ end of the HCV polyprotein. For this purpose, a full-length cDNA clone from HCV (H77, genotype 1a) was used, and results indicated that the introduction of NS5A targeted siRNA resulted in an inhibition of NS5A and core protein expression. Moreover, we observed that this siRNA effectively inhibited NS5A mediated activation of the IL-8 promoter. Taken together, our results demonstrated that siRNA was effective in inhibiting HCV protein expression, and may have therapeutic potential to limit HCV replication in chronically infected patients.

We have investigated oocyte development in Hydra vulgaris, a member of one of the oldest metazoan phyla. We show that oocyte determination involves a mechanism that establishes a subset of precursor interstitial cells competent to differentiate into oocytes. The oocyte is singled out from this subset and the competence of the remaining cells to become oocytes dramatically decreases as they adopt the alternative nurse cell fate. Progression through the nurse cell differentiation program requires the presence of the oocyte. When the oocyte is removed from the egg field, nurse cells abort their differentiation program, undergo apoptosis, and are phagocytosed and degraded by somatic epithelial cells. However, in the presence of the oocyte, nurse cells differentiate and enter an unusual apoptosis program where they are phagocytosed by the oocyte, but are not degraded. We show that the oocyte is able to induce this unusual apoptosis program in immature nurse cells that have not completed differentiation. A new model for oocyte development in Hydra is discussed.

Hepatitis C virus NS5A protein transcriptionally modulates cellular genes and promotes cell growth. NS5A is likely to exert its activity in concert with cellular factor(s). Using a yeast two-hybrid screen, we have demonstrated that NS5A interacts with the C-terminal end of a newly identified cellular transcription factor, SRCAP. The authenticity of this interaction was verified by a mammalian two-hybrid assay, in vitro pull-down experiment, and an in vivo coimmunoprecipitation assay in human hepatoma (HepG2) cells. An in vitro transient transfection assay demonstrated that SRCAP can efficiently activate transcription when recruited by the Gal4 DNA-binding domain to the promoter. However, down-regulation of p21 promoter activity by NS5A was enhanced following ectopic expression of SRCAP. Together these results suggest that the interaction of NS5A and SRCAP may be one of the mechanisms by which NS5A exerts its effect on cell growth regulation contributing to hepatitis C virus-mediated pathogenesis.

Aims: To assess and compare knowledge and awareness of colorectal cancer and breast cancer in a sample of the general population. Methods: Eleven hundred visitors to six different outpatient clinics, in a University Hospital, were given a study-specific questionnaire, based on educational material from the British Association of Cancer United Patients (CancerBACUP). The questionnaire consisted of 12 statements on the incidence, presentation, detection, treatment and prognosis of colorectal and breast cancer. Results: One thousand and sixty-eight individuals returned the questionnaire. One thousand and four completed questionnaires were analysed. The mean age (SD) of respondents was 50.1 (17.2) years, and the male to female ratio was 2:3. Respondents had read more about breast than about colorectal cancer (60.3% vs 32.4%, P

MBP-1, a c-myc promoter binding protein, is a mammalian transcription factor with intriguing properties including transcriptional repression of cellular genes. Recently, we have identified and characterized two different repressor domains of MBP-1. In this report, we have demonstrated that MBP-1 physically associates with histone deacetylase (HDAC), thus promoting formation of neucleosomes that inhibit transcription. Trichostatin A, an inhibitor of histone deacetylase, significantly reduces MBP-1-mediated transcriptional repression. However, MBP-1-mediated repression on c-myc promoter is resistant to histone deacetylase activity. Our results suggest that MBP-1 represses transcription by recruiting histone deacetylase as one of the mechanisms, whereas the other mechanism is resistant to HDAC activity and probably related to direct binding of promoter sequences or interaction through yet unidentified factor.

The aim of this study was to evaluate the safety and tolerability of 4 weeks administration of marimastat, and to seek evidence of biological activity as observed by changes in the endoscopic appearance of the gastric tumours. 35 patients with advanced, inoperable gastric or gastro-oesophageal tumours were recruited. The dose of marimastat was reduced from the starting dose of 50 mg twice daily (6 patients) to 25 mg once daily (29 patients). 31 completed the 28 day study period. Marimastat was generally well tolerated, with the principal treatment-related toxicity being pain and stiffness of the musculoskeletal system. These symptoms occurred more frequently at the higher-dose, and increased to involve a total of 13 patients (37%) with longer-term treatment. The events were usually rapidly reversible on drug discontinuation. 3 patients receiving prolonged treatment experienced more severe symptoms, with the development of skin thickening and contractures in the hands. At endoscopy, 10 patients showed an increased fibrotic cover of the tumour, 8 had decreased haemorrhagic appearance, and in at least 2 cases where comparative tumour histology was assessable, there was evidence of increased stromal fibrotic tissue.

Ion exchange resin displays prolonged gastric residence and uniform distribution over the gastric mucosa when given in a small volume of water to fasted subjects. The aim of this study was to explore factors which could influence the observed gastric retention, for example the quantity of resin administered, the fed state of the subject, and the surface charge of the resin. The study was performed as a single blind, three-way crossover in 12 healthy volunteers using gamma scintigraphy to visualize the distribution of the resin in the stomach. On the first two occasions each subject received either a 25 mg or 250 mg dose of cholestyramine (an anionic exchange resin) in 1 ml of water. On the last occasion each volunteer received 250 mg of cholestyramine coated with the inert polymer ethylcellulose, to determine if the gastric residence of the resin was influenced by the surface properties of the particles. For all formulations, half of the subjects were fed 4 h after dosing to determine the effects of inducing a fed pattern of motility on the gastric retention of the resin. Gastric retention was measured as the area under the stomach activity–time curve (AUC). Median AUC values (relative units) for the 25 mg, 250 mg and polymer coated 250 mg doses were 139.6, 199.6 and 146.0 respectively, for fasted subjects and 164.1, 256.9 and 176.1 for fed subjects. Approximately 20% of the resin persisted in the stomach for the entire 6 h of the study in every case, and this was distributed evenly throughout the fundus, body and antrum. Statistical analysis of the data showed no significant differences between the gastric emptying and distribution of any of the data sets. It can be concluded that the prolonged gastric residence and uniform distribution of ionic resins is not influenced by the dose size and that the binding of the dose to the mucosa is sufficiently strong to retain the dose during feeding 4 h after administration. The mechanism by which resin becomes mucoadherent is not clear; however, these results indicate that it is unlikely to be due to a charge-based attraction.

Hepatitis C virus (HCV) putative core protein has displayed many intriguing biological properties. Since tumor necrosis factor (TNF) plays an important role in controlling viral infection, in this study the effect of the core protein was investigated on the TNF-alpha induced apoptosis of human breast carcinoma cells (MCF7). HCV core protein when expressed inhibited TNF-alpha-induced apoptotic cell death unlike the control MCF7 cells, as determined by cell viability and DNA fragmentation analysis. Additionally, HCV core protein blocked the TNF-induced proteolytic cleavage of the death substrate poly(ADP-ribose) polymerase from its native 116-kDa protein to the characteristic 85-kDa polypeptide. Results from this study suggest that the HCV core protein plays a role in the inhibition of TNF-alpha-mediated cell death. Thus, the ability of core protein to inhibit the TNF-mediated apoptotic signaling pathway may provide a selective advantage for HCV replication, allowing for evasion of host antiviral defense mechanisms.

Matrix metalloproteinases have been shown to be important in tumour invasion and metastasis, and the use of matrix metalloproteinase inhibitors in animal models has suggested that these agents may be useful in the control of malignant disease. This article reports the results of an early clinical trial of batimastat, one of the first generation of metalloproteinase inhibitors, in patients with malignant ascites. The drug was well absorbed via the intraperitoneal route and associated with few side-effects. Furthermore, a response to treatment was seen in about half the evaluable patients with advanced malignant disease. The results suggest that further research on the use of matrix metalloproteinase inhibitors in patients with malignant disease is worthwhile.

Accumulating evidence indicates that a common set of genes and mechanisms regulates the developmental processes of a variety of triploblastic organisms despite large variation in their body plans. To what extent these same genes and mechanisms are also conserved among diploblasts, which arose earlier in metazoan evolution, is unclear. We have characterized a hydra homologue of the fork head/HNF-3 class of winged-helix proteins, termed budhead, whose expression patterns suggest a role(s) similar to that found in vertebrates. The vertebrate HNF-3 beta homologues are expressed early in embryogenesis in regions that have organizer properties, and later they have several roles, among them an important role in rostral head formation. In the adult hydra, where axial patterning processes are continuously active, budhead is expressed in the upper part of the head, which has organizer properties. It is also expressed during the formation of a new axis as part of the development of a bud, hydra's asexual form of reproduction. Expression during later stages of budding, during head regeneration and the formation of ectopic heads, indicates a role in head formation. It is likely that budhead plays a critical role in head as well as axis formation in hydra.

This article considers the management of the gastrointestinal bleeding patient up to the time of endoscopy and/or surgery. It deals with initial assessment, resuscitation, history taking, examination, and preparation for both endoscopy and surgery. Clinical detail is emphasized, and stress is placed on the adequate organization of a gastrointestinal bleeding unit.

We previously demonstrated that exogenous expression of MBP-1 induces rapid cell death in murine fibroblasts, and alters loss of anchorage-independent growth and tumorigenicity in human breast carcinoma cells. Here, we investigated the functional role of two different domains of MBP-1. A DNA-protein interaction study suggested that the amino-terminal half (amino acids 1–178) of MBP-1 possesses the c-myc P2 promoter binding activity. The same domain of MBP-1 also showed transcriptional repressor activity on c-myc promoter by in vitro transient expression assay. On the other hand, the carboxy terminal half (amino acids 190–335) of MBP-1 induced cell death in murine fibroblasts similar to full length MBP-1. Furthermore, exogenous protein expression from the carboxy terminal half of MBP-1 in human breast carcinoma (MCF-7) cells showed suppression of colony formation and loss of anchorage-independent growth. Results from this study suggest that MBP-1 exerts its biological effect through different functional domains.

The purpose of this study was to determine the effect of the gastrin receptor antagonist, CR2093, on basal and gastrin-stimulated growth of primary human colorectal adenocarcinomas and to relate this to gastrin receptor expression. Tumour cells, derived from surgical specimens by enzymatic disaggregation, were grown on matrices of type I collagen and irradiated fibroblasts. Gastrin receptor expression was measured by using a mouse monoclonal antibody directed against the gastrin receptor and an avidin-biotin immunocytochemical method. Increased growth in the presence of gastrin-17 (used at physiological concentrations and as assessed by [3H] thymidine uptake) was shown in 16/34 (47%) tumours. CR2093 significantly reversed this stimulated growth (P < 0.05, one way analysis of variance) in 9/16 (56.3%) of the tumours and inhibited the basal growth of 11/34 (32.4%). Basal growth inhibition was reversed by gastrin-17 in 82% (9/11) of tumours. Gastrin receptor expression was widespread, but was not related to the degree of growth response to gastrin, and there was no significant correlation between intensity of receptor expression and inhibition of basal growth by CR2093. In conclusion, both gastrin-stimulated and basal growth of primary human colorectal can be inhibited by gastrin receptor antagonism, but gastrin receptor expression does not predict the sensitivity of tumours to (i) the proliferative effects of gastrin or (ii) the inhibitory effects of a gastrin receptor antagonist on basal growth. Antigastrin agents may have clinical value in the treatment of gastrin-sensitive colorectal tumours, and gastrin receptor expression may be related to endogenous gastrin production by colorectal tumour cells.

The genomic region encoding the hepatitis C virus (HCV) core protein was cloned into a mammalian expression vector to study its role on the transcriptional regulation of cellular proto-oncogene and viral promoters. Using a transient transfection assay in human hepato-cellular carcinoma (HepG2) cells, we demonstrate that the HCV core protein activates the human c- myc , Rous sarcoma virus long terminal repeat (LTR), and simian virus 40 (SV40) early promoters; and suppresses the c- fos promoter and human immunodeficiency virus type 1 (HIV-1) LTR activity. The transcriptional regulation of cellular proto-oncogenes by the HCV core protein suggests possible involvement of the core protein in the deregulation of normal hepatocyte growth and hepatocarcinogenesis.

The Idaho National Engineering Laboratory (INEL) is performing research in support of the efforts of the U.S. Nuclear Regulatory Commission (NRC) regarding the ability of motor-operated valves (MOVs) to perform their design basis function, usually to close against specified flow and pressure loads. Before 1979, the nuclear industry was not aware that they had major problems with their MOVs. However, the Three Mile Island (TMI) accident revealed the seriousness of this issue when the failure of a PORV block valve (a motor-operated gate valve) contributed to the severity of the accident. The inability of the auxiliary feedwater gate valves at Davis-Besse to reopen after they were inadvertently closed in 1985 further confirmed the seriousness of this issue. This paper presents the results of testing sponsored by the NRC to assess valve and motor operator performance under varying pressure and fluid conditions. This effort included an examination of the methods used by the industry to predict the required stem force of a valve, and research to provide guidelines for the extrapolation of in situ test results to design basis conditions. Years ago, when most of these valves were originally installed, the industry used a set of equations to determine analytically that the valves' motor-operators were large enough and the control switches were set high enough to close the valves at their design basis conditions. Our research has identified several inconsistencies with the industry's existing gate valve stem force equation and has challenged the overly simplistic assumptions inherent in its use. This paper discusses the development of the INEL correlation, which serves as the basis for a method to bound the stem force necessary to close flexwedge gate valves whose operational characteristics have been shown to be predictable. As utilities undertake to provide assurance of their valves' operability, this ability to predict analytically the required stem force is especially important for valves that cannot be tested at design basis conditions. For such valves, the results of tests conducted at less severe conditions can be used with the INEL correlation to make the necessary prediction.

A description of the molecular make-up of the ancestral multicellular animal is emerging from the growing availability of molecular biological and biochemical data gleaned from the study of modern members of ancient groups of animals. We use the distributions of classes of transcription factors, signal transduction systems and other molecular innovations among metazoan phyla to infer some of the characteristics of the first animals.

Alternative splicing is used by the src protooncogene to derive two gene products, pp60c-src and pp60+. pp60+ is expressed exclusively in neurons, whereas pp60c-src is expressed in many tissues. The specific role of the src+ gene product in neurons is not yet understood. Expression of src+ mRNA begins early in neural development and is restricted to the neural plate in Xenopus embryos. Using a reverse transcription/polymerase chain reaction assay, we demonstrate that expression of src+ mRNA is dependent on neural induction. Src+ mRNA is expressed in animal cap ectoderm which is cocultured with mesoderm tissue, but not in ectoderm cultured alone. The protein kinase C (PKC) activator 12-O-tetradecanoylphorbol-13-acetate (TPA) induces src+ mRNA expression in cultured stage 10+ animal cap ectoderm. This induction is rapid, with src+ mRNA being detected within 1 hr of TPA addition. Only dorsal ectoderm tissue is competent to express src+ mRNA upon TPA treatment, and stage 10+ ectoderm tissue becomes unresponsive to TPA after 4 hr in culture. TPA-dependent induction of src+ mRNA in ectoderm tissue is not blocked by cycloheximide and therefore is not dependent on protein synthesis.

Valve test programs sponsored by the United States Nuclear Regulatory Commission (USNRC) and conducted by researchers from the Idaho National Engineering Laboratory (INEL) have yielded important insights concerning motor-operated valve operator sizing and in situ testing. The most significant of these test programs was a full-scale, high-energy qualification and flow-interruption gate valve test program conducted in the spring of 1988. For this program, we modified two representative 6 in., 900 lb valve assemblies to include a high-temperature load cell in each of the valve stems to directly measure stem thrust. Instrumentation in the flow loop and on the motor operators measured the important responses and parameters. At various times during the test program, each of the currently popular diagnostic test systems was installed to monitor the performance of the valve motor operators. The valves were subjected to the hydraulic and leakage testing requirements specified in ANSI B16.41 (QV-4) and to flow interruption (valve closure) testing at boiling water reactor (BWR) temperatures and pressures at line break conditions. Results show that for the tested valves, the variables used in current industry motor operator sizing equations underpredict actual valve thrust requirements at high temperature loadings; for one valve design, the equation may need an additional term to account for nonlinear performance. Results also show that the thrusts needed to close the valves were sensitive to the fluid temperature, and that the results of testing at lower pressures, temperatures, and flows cannot be extrapolated to design basis conditions.

Summary Current evidence would not support the notion that casevolume in itself is important for achieving good results in cancer surgery. It is, however, becoming increasingly clear that specialist interest is important, and it is not too difficult to guess at the reasons for this seeming paradox. In areas where surgical skill is paramount, such as in rectal cancer surgery, the specialist will be familiar with the relevant anatomy and techniques so that good results will be achieved, even though relatively small numbers of cancers may be treated. In conditions where a multi-disciplinary approach is vital, such as breast or ovarian cancer, the specialist surgeon will be acutely aware of the necessity for non-surgical forms of treatment. The generalist, on the other hand, may not appreciate the nuances of surgical technique or the availability of adjuvant therapy which are required to achieve the best results. Thus, despite a high case volume he or she might obtain suboptimal results, either through ignorance or through pure haste engendered by pressure of work.

In this retrospective review of 164 consecutive patients with malignant ascites it has been shown that ovarian ascites accounts for 28% of the total and is associated with a significantly improved survival compared with other groups (P

Study objectives: We determine the frequency in which trauma activations were associated with operative management by a trauma surgeon and whether currently used American College of Surgeons Committee on Trauma (ACS-COT) guidelines of out-of-hospital variables could predict such findings to help better prioritize the urgency of trauma surgeon presence during trauma activations. Methods: This was a retrospective analysis of a prospectively recorded trauma registry of all trauma activations from January 1, 1997, to December 31, 2002. Univariate analyses of out-of-hospital variables recorded in the trauma registry were evaluated in a university-based Level I trauma center serving a region of approximately 3 million people, with an annual emergency department census of 53,000 patients. All trauma activations were analyzed to determine whether operative management was performed. Subjects were then subdivided into 3 groups, defined as emergency (operative management 1 to 4 hours). In all cases, the surgical specialist and disposition were noted. Out-of-hospital variables were evaluated to determine predictive values of emergency and urgent surgical intervention. Results: There were 5,001 trauma activations during the study period. Thirty percent went to the operating room, with 4% emergency, 8% urgent, and 18% semiurgent. Orthopedics performed operative management on 37% of all cases, followed by general surgery at 32%. For emergency cases, general surgery performed operative management on 69%, followed by neurosurgery on 11%. For urgent cases, general surgery performed operative management on 38% and neurosurgery on 25%. For semiurgent cases, orthopedics took 53%, and general surgery took 22%. Predictors of emergency operative management include systolic blood pressure less than 90 mm Hg (RR 3.00; 95% confidence interval [CI] 2.0 to 4.4 mm Hg); penetrating trauma (RR 8.0; 95% CI 6.1 to 10.6), and blunt trauma (RR 0.12; 95% CI 0.09 to 0.17). Predictors of urgent operative management include penetrating trauma (RR 2.30; 95% CI 1.88 to 2.82). Variables not correlated with operative management were pulse rate, respiratory rate, Glasgow Coma Scale score, blunt trauma, and age. Conclusion: Although eventual operative management of trauma activations is common, emergency operative management occurred in only 4% of patients. Predictors of emergency operative management were systolic blood pressure less than 90 mm Hg and penetrating trauma. Currently accepted ACS-COT trauma guidelines of out-of-hospital variables poorly predicted the need for emergency, urgent, and semiurgent operative management. Upcoming further multivariate and classification and regression tree analysis is necessary to better classify trauma patients into various risk categories for any urgent surgical intervention.

Background: Our 2-armed multi-centre randomized controlled trial (RCT) reported a significantly reduced postoperative pain and higher patient acceptability following stapled hemorrhoidopexy (SH) but without similar advantage for post-treatment residual prolapse or retreatment rates. In this parallel health economics study, we aimed to determine the costeffectiveness of SH from a hospital perspective when compared with Ferguson hemorrhoidectomy (FH). Methods: After informed consent and randomization, 182-patients with symptomatic hemorrhoids (grades II, III, IV) underwent either SH (91) or FH and were followed for up to 1-year (6, 12, 24, 48-weeks) after operation. All health-care resource costs for the initial treatment and follow-up events were recorded prospectively at individual patient level. Quality of life (QoL) was assessed at baseline, and at follow-up using SF36v2 questionnaire and QALY's generated using SF-6D algorithm. An incremental cost of avoiding a recurrence was calculated along with an incremental cost per QALY for SH. Differences between groups were based on linear regression adjusting for baseline scores. Results: At 1-year follow-up, a total of 18 (20.7%) patients in SH group had clinical recurrence compared to 9 (11.5%) in FH group (OR= 2, 95% CI 0.8405-4.7593). 12-SH patients required retreatment for residual symptoms compared to 5 in FH group. Re-treatment for residual prolapse was significantly higher in SH group (8 vs. 1; SH vs. FH; p=0.027 X2-test). At 1year the mean difference in QALY's was non-significant (0.7877 vs. 0.7938, SH vs. FH; p= 0.877 MWU-test). The extra mean cost (£312.51) incurred for SH was due to the additional cost for the single use custom-designed circular stapler. The cost per unit of successful outcome was less in FH group compared to SH group (£770.75 vs. 1184.45; FH vs. SH). Conclusions: Stapled hemorrhoidopexy offers significant advantages of lower post-operative pain but is associated with significantly higher residual prolapse rates requiring re-operation. The mean cost of stapled hemorrhoidopexy was higher compared to Ferguson hemorrhoidectomy and this was largely explained by the cost of the single use stapler. Furthermore, the study failed to demonstrate any significant cost-effectiveness advantage for stapled hemorrhoidopexy when compared to Ferguson hemorrhoidectomy.