RESUMEN
BACKGROUND: Changes in bacterial populations termed "dysbiosis" are thought central to ulcerative colitis (UC) pathogenesis. In particular, the possibility that novel Helicobacter organisms play a role in human UC has been debated but not comprehensively investigated. The aim of this study was to develop a molecular approach to investigate the presence of Helicobacter organisms in adults with and without UC. METHODOLOGY/PRINCIPAL FINDINGS: A dual molecular approach to detect Helicobacter was developed. Oligonucleotide probes against the genus Helicobacter were designed and optimised alongside a validation of published H. pylori probes. A comprehensive evaluation of Helicobacter genus and H. pylori PCR primers was also undertaken. The combined approach was then assessed in a range of gastrointestinal samples prior to assessment of a UC cohort. Archival colonic samples were available from 106 individuals for FISH analysis (57 with UC and 49 non-IBD controls). A further 118 individuals were collected prospectively for dual FISH and PCR analysis (86 UC and 32 non-IBD controls). An additional 27 non-IBD controls were available for PCR analysis. All Helicobacter PCR-positive samples were sequenced. The association between Helicobacter and each study group was statistically analysed using the Pearson Chi Squared 2 tailed test. Helicobacter genus PCR positivity was significantly higher in UC than controls (32 of 77 versus 11 of 59, pâ=â0.004). Sequence analysis indicated enterohepatic Helicobacter species prevalence was significantly higher in the UC group compared to the control group (30 of 77 versus 2 of 59, p<0.0001). PCR and FISH results were concordant in 74 (67.9%) of subjects. The majority of discordant results were attributable to a higher positivity rate with FISH than PCR. CONCLUSIONS/SIGNIFICANCE: Helicobacter organisms warrant consideration as potential pathogenic entities in UC. Isolation of these organisms from colonic tissue is needed to enable interrogation of pathogenicity against established criteria.
Asunto(s)
Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/etiología , Infecciones por Helicobacter/complicaciones , Helicobacter/aislamiento & purificación , Intestinos/microbiología , Hígado/microbiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Estudios de Cohortes , Colitis Ulcerosa/epidemiología , Colitis Ulcerosa/microbiología , Femenino , Helicobacter/fisiología , Infecciones por Helicobacter/diagnóstico , Infecciones por Helicobacter/epidemiología , Infecciones por Helicobacter/patología , Humanos , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Intestinos/patología , Hígado/patología , Masculino , Técnicas Microbiológicas , Persona de Mediana Edad , Técnicas de Diagnóstico Molecular , Estudios de Validación como Asunto , Adulto JovenRESUMEN
Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. Inflammatory activity within the stroma of invasive colorectal tumours is known to be a key predictor of disease activity with type, density and location of immune cells impacting on patient prognosis. To date, there has been no report of inflammatory phenotype within pre-malignant human colonic adenomas. Assessing the stromal microenvironment and particularly, inflammatory activity within colorectal neoplastic lesions is central to understanding early colorectal carcinogenesis. Inflammatory cell infiltrate was assessed by immunohistochemistry in paired colonic adenoma and adjacent normal colonic mucosa samples, and adenomas exhibiting increasing degrees of epithelial cell dysplasia. Macrophage phenotype was assessed using double stain immunohistochemistry incorporating expression of an intracellular enzyme of function. A targeted array of inflammatory cytokine and receptor genes, validated by RT-PCR, was used to assess inflammatory gene expression. Inflammatory cell infiltrates are a key feature of sporadic adenomatous colonic polyps with increased macrophage, neutrophil and T cell (specifically helper and activated subsets) infiltration in adenomatous colonic polyps, that increases in association with characteristics of high malignant potential, namely, increasing degree of cell dysplasia and adenoma size. Macrophages within adenomas express iNOS, suggestive of a pro-inflammatory phenotype. Several inflammatory cytokine genes (CXCL1, CXCL2, CXCL3, CCL20, IL8, CCL23, CCL19, CCL21, CCL5) are dysregulated in adenomas. This study has provided evidence of increased inflammation within pre-malignant colonic adenomas. This may allow potential mechanistic pathways in the initiation and promotion of early colorectal carcinogenesis to be identified.
Asunto(s)
Neoplasias Colorrectales/patología , Lesiones Precancerosas/patología , Microambiente Tumoral , Adenoma/genética , Adenoma/patología , Pólipos del Colon/genética , Pólipos del Colon/patología , Citocinas/genética , Regulación de la Expresión Génica , Humanos , Inflamación/etiología , Inflamación/patología , Linfocitos Infiltrantes de Tumor/inmunología , Macrófagos/inmunología , PronósticoRESUMEN
Vaginismus is generally described as an involuntary contraction of the vaginal musculature, which usually results in the failure of penetration. Despite a lack of consensus as to the exact definition, prevalence rates vary between 4.2% and 42%. It is commonly diagnosed at both gynaecological and psychosexual clinics. The majority of studies and treatment options concentrate on the premenopausal age group. It is accepted that even within this age group, the diagnosis is often incorrect as symptoms can be confused with dyspareunia and other sexual pain disorders. There is no literature discussing vaginismus in the postmenopausal patient, despite evidence that an active sex life is important to the majority of women, irrespective of age. It is known that the majority of women do not report difficulties in their sex life and it may be that the older patient is more embarrassed at disclosing any such difficulties. This review aims to highlight the possible causes of vaginismus in this older age group and to aid the clinician in asking the appropriate questions, performing the appropriate examination and suggesting possible treatment options.
Asunto(s)
Médicos Generales , Perimenopausia/fisiología , Posmenopausia/fisiología , Vaginismo/diagnóstico , Vaginismo/etiología , Dispareunia/diagnóstico , Terapia de Reemplazo de Estrógeno , Femenino , Humanos , Guías de Práctica Clínica como Asunto , Conducta Sexual/fisiología , Conducta Sexual/psicología , Vagina/fisiología , Vaginismo/clasificación , Vaginismo/epidemiologíaRESUMEN
Colonization of the gastric mucosa by Helicobacter pylori can lead to serious clinical outcomes, including gastric cancer. Toll-like receptors (TLRs) play an important role in the host response to H. pylori through the recognition of pathogen-associated molecular patterns. TLR9, in particular, is partly responsible for initiating bacterial induced immunity by binding unmethylated CpG-DNA, which is abundant in bacteria. A well-documented single nucleotide polymorphism (SNP) within the TLR9 promoter (TLR9 -1237T/C), is associated with a variety of inflammatory disorders, including allergic asthma, inflammatory bowel disease, and atopy. Analysis of the TLR9 promoter gene sequence has shown that carriage of the variant "C" allele at position -1237 creates a potential NF-kappaB binding site that would theoretically increase the transcriptional activity of the gene. In this study, we report that the TLR9 -1237 C allele was significantly associated with the development of H. pylori-induced premalignant gastric changes. Functional analysis of the SNP, supporting the data generated from the genetic association study, showed that carriage of the C allele increased TLR9 transcriptional activity driven mainly by activation of NF-kappaB. Collectively, these findings confirm that the TLR9 -1237T/C polymorphism is a risk factor for the development of H. pylori-induced premalignant gastric changes and provide a plausible mechanistic explanation.
Asunto(s)
Infecciones por Helicobacter/genética , Infecciones por Helicobacter/inmunología , Helicobacter pylori/inmunología , FN-kappa B/inmunología , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/inmunología , Expresión Génica , Frecuencia de los Genes , Infecciones por Helicobacter/patología , Humanos , FN-kappa B/metabolismo , Unión Proteica , Escocia , Receptor Toll-Like 9/metabolismo , Regulación hacia ArribaRESUMEN
There are vast numbers of bacteria present within the human colon that are essential for the host's well being in terms of nutrition and mucosal immunity. While certain members of the colonic microbiota have been shown to promote the host's health there are also numerous studies that have implicated other members of the colonic microbiota in the development of colorectal cancer, a prominent malignancy within the western world. In this review we consider the evidence for the role of bacteria in colorectal cancer from molecular and animal model studies. We focus on some of the mechanisms by which the colonic microbiota drives the progression towards colorectal malignancy including generation of reactive metabolites and carcinogens, alterations in host carbohydrate expression and induction of chronic mucosal inflammation.