Primary Signet-Ring Carcinoma (Linitus Plastica) of the Colorectum presenting as Subacute Intestinal Obstruction

Primary Signet-ring cell carcinoma (Linitus Plastica) of the colon and rectum is a rare form of adenocarcinoma of the large intestine and has been reported to have an extremely poor prognosis. We report a case of Primary Signet-ring cell carcinoma of the colorectum in a thirty one year old man presented in Surgical OPD of our hospital with chief complaints of persistent pain in abdomen and vomiting since two days. Since the prognosis of primary signet ring cell carcinoma (SRCC) is extremely poor (in view of more malignant behavior than ordinary colorectal carcinoma), early diagnosis and aggressive treatment strategy are necessary

ST-Producing E. coli Oppose Carcinogen-Induced Colorectal Tumorigenesis in Mice.

There is a geographic inequality in the incidence of colorectal cancer, lowest in developing countries, and greatest in developed countries. This disparity suggests an environmental contribution to cancer resistance in endemic populations. Enterotoxigenic bacteria associated with diarrheal disease are prevalent in developing countries, including enterotoxigenic E. coli (ETEC) producing heat-stable enterotoxins (STs). STs are peptides that are structurally homologous to paracrine hormones that regulate the intestinal guanylyl cyclase C (GUCY2C) receptor. Beyond secretion, GUCY2C is a tumor suppressor universally silenced by loss of expression of its paracrine hormone during carcinogenesis. Thus, the geographic imbalance in colorectal cancer, in part, may reflect chronic exposure to ST-producing organisms that restore GUCY2C signaling silenced by hormone loss during transformation. Here, mice colonized for 18 weeks with control E. coli or those engineered to secrete ST exhibited normal growth, with comparable weight gain and normal stool water content, without evidence of secretory diarrhea. Enterotoxin-producing, but not control, E. coli, generated ST that activated colonic GUCY2C signaling, cyclic guanosine monophosphate (cGMP) production, and cGMP-dependent protein phosphorylation in colonized mice. Moreover, mice colonized with ST-producing E. coli exhibited a 50% reduction in carcinogen-induced colorectal tumor burden. Thus, chronic colonization with ETEC producing ST could contribute to endemic cancer resistance in developing countries, reinforcing a novel paradigm of colorectal cancer chemoprevention with oral GUCY2C-targeted agents

Enteric dysfunctions in experimental Parkinson's disease: alterations of excitatory cholinergic neurotransmission regulating colonic motility in rats

Parkinson's disease (PD) is frequently associated with gastrointestinal symptoms, mostly represented by constipation and defecatory dysfunctions. This study examined the impact of central dopaminergic denervation, induced by injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, on distal colonic excitatory cholinergic neuromotor activity in rats. Animals were euthanized 4 and 8 weeks after 6-OHDA injection. In vivo colonic transit was evaluated by radiological assay. Electrically and carbachol-induced cholinergic contractions were recorded in vitro from longitudinal and circular muscle colonic preparations, while acetylcholine levels were assayed in their incubation media. Choline acetyltransferase (ChAT), HuC/D (pan-neuronal marker), muscarinic M2 and M3 receptors. As compared with control rats, at week 4 6-OHDA-treated animals displayed the following changes: decreased in vivo colonic transit rate; impaired electrically evoked neurogenic cholinergic contractions; enhanced carbachol-induced contractions; decreased basal and electrically stimulated acetylcholine release from colonic tissues; decreased ChAT immunopositivity in the neuromuscular layer; unchanged density of HuC/D immunoreactive myenteric neurons; increased expression of colonic muscarinic M2 and M3 receptors. The majority of such alterations were detected also at week 8 post-6-OHDA injection. These findings indicate that central nigrostriatal dopaminergic denervation is associated with an impaired excitatory neurotransmission characterized by a loss of myenteric neuronal ChAT positivity and decrease in acetylcholine release, resulting in a dysregulated smooth muscle motor activity, which likely contributes to the concomitant decrease in colonic transit rate

Peripheral Mediators of Colorectal Nociception and Sensitization

Several ion channels are thought to facilitate colorectal afferent neuron sensitization, which contributes to abdominal pain in irritable bowel syndrome (IBS). In the present work, I hypothesized that two such channels – TRPV1 and P2X3 – cooperate to mediate colorectal pain and hypersensitivity. To test this, I employed TRPV1-P2X3 double knockout (TPDKO) mice and pharmacological antagonists and evaluated combined channel contributions to whole- organism responses to colorectal distension (CRD) and afferent fiber responses to colorectal stretch. Baseline responses to CRD were unexpectedly greater in TPDKO compared with control mice, but zymosan-produced CRD hypersensitivity was absent in TPDKO mice. Relative to control mice, proportions of afferent mechano-sensitive and -insensitive classes were not different in TPDKO mice. Whereas responses of mucosal and serosal class afferents to mechanical probing were unaffected, responses of muscular (but not muscular/mucosal) afferents to stretch were significantly attenuated in TPDKO mice as was sensitization by inflammatory soup of both muscular and muscular/mucosal afferents. In pharmacological studies, the TRPV1 antagonist A889425 and P2X3 antagonist TNP-ATP, alone and in combination, applied onto stretch-sensitive afferent endings attenuated afferent responses to stretch; combined antagonism produced greater attenuation. In the aggregate, these observations suggest that: (1) genetic manipulation of TRPV1 and P2X3 leads to reduction in colorectal mechanosensation peripherally and compensatory changes and/or disinhibition of other channels centrally and (2) combined pharmacological antagonism produces more robust attenuation of mechanosensation peripherally than single antagonism. The relative importance of these channels appears to be enhanced in hypersensitivity, highlighting the potential utility of multi-target pharmacotherapy in IBS

APC-β-catenin-TCF signaling silences the intestinal guanylin-GUCY2C tumor suppressor axis.

Sporadic colorectal cancer initiates with mutations in APC or its degradation target β-catenin, producing TCF-dependent nuclear transcription driving tumorigenesis. The intestinal epithelial receptor, GUCY2C, with its canonical paracrine hormone guanylin, regulates homeostatic signaling along the crypt-surface axis opposing tumorigenesis. Here, we reveal that expression of the guanylin hormone, but not the GUCY2C receptor, is lost at the earliest stages of transformation in APC-dependent tumors in humans and mice. Hormone loss, which silences GUCY2C signaling, reflects transcriptional repression mediated by mutant APC-β-catenin-TCF programs in the nucleus. These studies support a pathophysiological model of intestinal tumorigenesis in which mutant APC-β-catenin-TCF transcriptional regulation eliminates guanylin expression at tumor initiation, silencing GUCY2C signaling which, in turn, dysregulates intestinal homeostatic mechanisms contributing to tumor progression. They expand the mechanistic paradigm for colorectal cancer from a disease of irreversible mutations in APC and β-catenin to one of guanylin hormone loss whose replacement, and reconstitution of GUCY2C signaling, could prevent tumorigenesis

Purinergic mechanosensory transduction and visceral pain

In this review, evidence is presented to support the hypothesis that mechanosensory transduction occurs in tubes and sacs and can initiate visceral pain. Experimental evidence for this mechanism in urinary bladder, ureter, gut, lung, uterus, tooth-pulp and tongue is reviewed. Potential therapeutic strategies are considered for the treatment of visceral pain in such conditions as renal colic, interstitial cystitis and inflammatory bowel disease by agents that interfere with mechanosensory transduction in the organs considered, including P2X(3) and P2X(2/3) receptor antagonists that are orally bioavailable and stable in vivo and agents that inhibit or enhance ATP release and breakdown

Transcript expression of vesicular glutamate transporters in lumbar dorsal root ganglia and the spinal cord of mice – Effects of peripheral axotomy or hindpaw inflammation

Using specific riboprobes, we characterized the expression of vesicular glutamate transporter (VGLUT)1–VGLUT3 transcripts in lumbar 4–5 (L4–5) dorsal root ganglions (DRGs) and the thoracolumbar to lumbosacral spinal cord in male BALB/c mice after a 1- or 3-day hindpaw inflammation, or a 7-day sciatic nerve axotomy. Sham animals were also included. In sham and contralateral L4–5 DRGs of injured mice, VGLUT1-, VGLUT2- and VGLUT3 mRNAs were expressed in ∼45%, ∼69% or ∼17% of neuron profiles (NPs), respectively. VGLUT1 was expressed in large and medium-sized NPs, VGLUT2 in NPs of all sizes, and VGLUT3 in small and medium-sized NPs. In the spinal cord, VGLUT1 was restricted to a number of NPs at thoracolumbar and lumbar segments, in what appears to be the dorsal nucleus of Clarke, and in mid laminae III–IV. In contrast, VGLUT2 was present in numerous NPs at all analyzed spinal segments, except the lateral aspects of the ventral horns, especially at the lumbar enlargement, where it was virtually absent. VGLUT3 was detected in a discrete number of NPs in laminae III–IV of the dorsal horn. Axotomy resulted in a moderate decrease in the number of DRG NPs expressing VGLUT3, whereas VGLUT1 and VGLUT2 were unaffected. Likewise, the percentage of NPs expressing VGLUT transcripts remained unaltered after hindpaw inflammation, both in DRGs and the spinal cord. Altogether, these results confirm previous descriptions on VGLUTs expression in adult mice DRGs, with the exception of VGLUT1, whose protein expression was detected in a lower percentage of mouse DRG NPs. A detailed account on the location of neurons expressing VGLUTs transcripts in the adult mouse spinal cord is also presented. Finally, the lack of change in the number of neurons expressing VGLUT1 and VGLUT2 transcripts after axotomy, as compared to data on protein expression, suggests translational rather than transcriptional regulation of VGLUTs after injury.Fil: Malet, Mariana. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Vieytes, C. A.. Universidad Austral. Facultad de Ciencias Biomédicas; ArgentinaFil: Lundgren, K. H.. University of Cincinnati; Estados UnidosFil: Seal, R. P.. University of Pittsburgh; Estados UnidosFil: Tomasella, María Eugenia. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Seroogy, K. B.. University of Cincinnati; Estados UnidosFil: Hökfelt, T.. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Gebhart, G. F.. University of Pittsburgh; Estados UnidosFil: Brumovsky, Pablo Rodolfo. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Pittsburgh; Estados Unido

The Cancer Transition in Japan since 1951

The overall trend of cancer mortality in Japan has been decreasing since the 1960s (age-standardized death rates for ages 30-69), though trends differ enormously among various forms of the disease. Cancer mortality was heavily influenced by Japanese postwar economic recovery, which led to improved living conditions and better control of infectious agents known to cause some common forms of cancer (stomach, cervical). However, Japanese wealth and development have also been associated with risky personal behaviors (smoking, drinking) and other conditions, leading to increases in cancers with no known or else very weak links to infection. This shift away from infectious and toward non-infectious causes of prevalent forms of cancers is called the "cancer transition," by analogy to Omran's "epidemiologic transition." We suggest that the cancer transition described here in the case of Japan must be a part of efforts to revise and update the epidemiologic transition, which should incorporate new knowledge about the role of infection in chronic disease morbidity and mortality.cancer, cancer transition, epidemiologic transition, health, health and development, infectious diseases, Japan, mortality, non-infectious disease

The excess burden of cancer in men in the UK

In general men are at significantly greater risk than women from nearly all of the common cancers that occur in both sexes (with the exception of breast cancer) (White 2009, Wilkins 2006, DH 2007). This report will consider the current overall burden of cancer among men in the UK, estimated from the latest statistics, and outline the extent of the differences between the sexes. All figures and calculations reported here are based on data extracted from the Cancer Research UK CancerStats web pages extracted in June 2009 (Cancer Research UK, 2009)

Identification of the Visceral Pain Pathway Activated by Noxious Colorectal Distension in Mice

In patients with irritable bowel syndrome, visceral pain is evoked more readily following distension of the colorectum. However, the identity of extrinsic afferent nerve pathway that detects and transmits visceral pain from the colorectum to the spinal cord is unclear. In this study, we identified which extrinsic nerve pathway(s) underlies nociception from the colorectum to the spinal cord of rodents. Electromyogram recordings were made from the transverse oblique abdominal muscles in anesthetized wild type (C57BL/6) mice and acute noxious intraluminal distension stimuli (100–120 mmHg) were applied to the terminal 15 mm of colorectum to activate visceromotor responses (VMRs). Lesioning the lumbar colonic nerves in vivo had no detectable effect on the VMRs evoked by colorectal distension. Also, lesions applied to the right or left hypogastric nerves failed to reduce VMRs. However, lesions applied to both left and right branches of the rectal nerves abolished VMRs, regardless of whether the lumbar colonic or hypogastric nerves were severed. Electrical stimulation applied to either the lumbar colonic or hypogastric nerves in vivo, failed to elicit a VMR. In contrast, electrical stimulation (2–5 Hz, 0.4 ms, 60 V) applied to the rectum reliably elicited VMRs, which were abolished by selective lesioning of the rectal nerves. DiI retrograde labeling from the colorectum (injection sites 9–15 mm from the anus, measured in unstretched preparations) labeled sensory neurons primarily in dorsal root ganglia (DRG) of the lumbosacral region of the spinal cord (L6-S1). In contrast, injection of DiI into the mid to proximal colon (injection sites 30–75 mm from the anus, measured in unstretched preparations) labeled sensory neurons in DRG primarily of the lower thoracic level (T6-L2) of the spinal cord. The visceral pain pathway activated by acute noxious distension of the terminal 15 mm of mouse colorectum is transmitted predominantly, if not solely, through rectal/pelvic afferent nerve fibers to the spinal cord. The sensory neurons of this spinal afferent pathway lie primarily in the lumbosacral region of the spinal cord, between L6 and S1