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Biomedical subjects

M J Farthing

Publications and source records attributed to M J Farthing.

At least 19 recordsLinked to original sources
PubMed2001

Treatment of gastrointestinal viruses.

The most common enteric viruses responsible for diarrhoea are rotavirus, enteric adenoviruses, caliciviruses including the Norwalk agent and astrovirus. These infections are usually mild to moderate in severity, self-limiting and of short duration and thus, specific antiviral therapy is not recommended. The standard management of these infections is restoration of fluid and electrolyte balance and then maintenance of hydration until the infection resolves. WHO oral rehydration therapy (ORT) was introduced about 30 years ago and has saved the lives of many infants and young children. During the last 10 years it has become evident that the efficacy of ORT can be increased by reducing the osmolality of the WHO oral rehydration solution (ORS) to produce a relatively hypotonic solution. Hypotonic ORS appears to be safe and effective in all forms of acute diarrhoea in childhood. Complex substrate ORS, which is also usually hypotonic, has been shown to have increased efficacy in cholera but not in other bacterial or viral diarrhoeas. Nevertheless, the scientific rationale for using rice or resistant starch as substrate in ORS is of physiological interest. Other treatments such as hyperimmune bovine colostrum, probiotics and antiviral agents are largely experimental and have not been introduced into routine clinical practice. Cytomegalovirus (CMV) infection of the gastrointestinal tract occurs mainly in the immunocompromised although it has been reported in immunocompetent individuals. CMV infects both the oesophagus and colon to produce oesophagitis, often with discrete ulcers, and colitis, respectively. Both conditions can be treated with ganciclovir or foscarnet. Failure to respond to monotherapy is an indication to use both agents concurrently.

Antiviral Agents↗
PubMed2001

Rigorous surveillance protocol increases detection of curable cancers associated with Barrett's esophagus.

Esophageal adenocarcinoma is increasing in incidence and has a high mortality unless detected early. Barrett's esophagus is the only known risk factor for this cancer; however, whether endoscopic surveillance reduces morbidity and mortality is controversial. Endoscopic cancer surveillance programes for Barrett's esophagus are not routinely practiced in the UK, and this is the first study to examine whether a rigorous surveillance protocol increases the detection rate of early oesophageal cancer. All patients with a diagnosis of Barrett's esophagus or associated adenocarcinoma attending Havering Hospitals NHS Trust between 1992 and 1998 were included. A retrospective analysis was made of patients undergoing informal surveillance (96 patients, 1992-1997) and a prospective analysis was conducted following the implementation of a rigorous protocol (108 patients, 1997-1998). Over the same time periods Barrett's associated cancers diagnosed in patients not undergoing surveillance were analyzed (262 patients 1992-1997, 98 patients 1997-1998). From 1992 to 1997, one case of high-grade dysplasia was detected (N = 96, 1%). From 1997 to 1998, two cancers and three high-grade dysplasias were detected during rigorous surveillance (N = 108, 4.6%). Three of these patients have had curative esophagectomies (one high-grade dysplasia and two T1,N0,M0 tumors). In 1992-1997, 10 patients were found to have cancer in previously undiagnosed Barrett's esophagus (N = 262, 3.8%). Of 3/10 cancers treated surgically, one patient had a curative procedure (T1,N0,M0). In 1997-1998, nine patients were found to have de novo Barrett's esophagus cancer (N = 88, 10.2%) and three had curative resections (T1,N0,M0). Two of the patients with T1 lesions had no endoscopic evidence of cancer but were detected as a result of the multiple biopsy protocol. In conclusion, a rigorous biopsy protocol increases the detection of early cancer in Barrett's esophagus.

Adenocarcinoma↗
PubMed2001

Lack of evidence for small intestinal mucosal T-cell activation as a pathogenic mechanism in African HIV-associated enteropathy.

The role of mucosal T-cell activation in HIV-associated enteropathy is uncertain. Twenty Zambian patients with AIDS and chronic diarrhea were studied, as were nine controls. Distal duodenal biopsies were taken at endoscopy. Morphometric analysis and dual color immunofluorescence staining were performed. Villous height was reduced [177 (118-228) vs 305 (244-358) microm P = 0.002] and crypt depth increased [220 (164-202) vs 194 (164-202) microm P = 0.008] in AIDS patients compared to controls. CD3+CD4+ T cells were reduced in AIDS patients compared to controls [12.9 (5.7-25.2) vs 47.6 (33.4-65.5)% P = 0.04]. There was no significant difference in expression of CD8, CD25, CD69, HML-1, or HLA-DR on T cells between the AIDS patients and controls, with the exception of CD3+HML-1+ cells, which were increased in AIDS patients (P = 0.05). Small intestinal T-cell activation was similar between AIDS patients and controls. We conclude, therefore, that this mechanism is not likely to be important in the pathogenesis of HIV-associated enteropathy.

Adult↗
PubMed2001

Changing patterns of sedation use for routine out-patient diagnostic gastroscopy between 1989 and 1998.

BACKGROUND: Knowledge of sedation trends for upper gastrointestinal endoscopy is important for health service planning, particularly in view of rapidly increasing demands on endoscopy services. However, no data are available on sedation trends in Britain over the past 10 years. AIM: To determine sedation use for routine gastroscopy in a single endoscopy unit between 1989 and 1998. METHODS: This was a retrospective study of 9795 consecutive adults (mean age 56 years, range 18-100 years; 4512 females) who had undergone a gastroscopy between 1989 and 1998. Clinical, pharmacological and endoscopic data were retrieved from a computerized database. RESULTS: Over the 10-year study period, the sedation rate remained constant for patients undergoing therapeutic endoscopy (P=0.99) and those undergoing in-patient diagnostic examinations (P=0.63). In contrast, the sedation rate for out-patient diagnostic endoscopy decreased by 54%, from a high of 70% in 1990 to 32% in 1998 (P < 0.0001). Logistic regression analysis showed that the decline in sedation use was greater in females (P < 0.0001) than males and in procedures performed by non-consultant compared to consultant staff (P=0.01). CONCLUSIONS: If our results form part of a national trend, they will have important implications for cardiopulmonary monitoring strategies, recovery room practices and for complication rates due to the use of sedation for upper gastrointestinal endoscopy.

Adolescent↗
PubMed2001

Impaired bioavailability of vitamin A in adults and children with persistent diarrhoea in Zambia.

BACKGROUND: We have previously demonstrated a strong relationship between low serum retinol concentration and mortality in Zambian AIDS patients with diarrhoea, but were unable to detect any benefit from oral micronutrient supplementation. AIM: To test the hypothesis that this is related to impaired availability of vitamin A, we analysed serum retinol concentration changes over 6 h following oral mega-dose therapy (60, 120 or 180 mg retinol). METHODS: Twenty-four men without diarrhoea, 15 adults with persistent diarrhoea and 11 children (six girls, five boys) with persistent diarrhoea were studied. RESULTS: Men with persistent diarrhoea had lower baseline serum retinol concentrations (median 0.39 micromol/L, interquartile range 0.21-0.56) than controls (median 1.16 micromol/L, interquartile range 0.84-1.47; P=0.0003). After 60 mg retinol, the rise in serum retinol in HIV seropositive controls (median 0.63 micromol/L, interquartile range 0.35-0.77) did not differ significantly from that observed in HIV seronegative controls (median 0.35 micromol/L, interquartile range - 0.04-0.56; P=0.20). Increasing the dose to 120 mg or 180 mg retinol did not enhance the increase in serum retinol concentration. The increase in serum retinol was less in adults with persistent diarrhoea (median 0.25 micromol/L, interquartile range 0.04-0.35) and in children (median 0.11 micromol/L, interquartile range 0.04-0.46) than in men without diarrhoea (median 0.44 micromol/L, interquartile range 0.26-0.74; P=0.03). Adults and children with diarrhoea had greater losses of retinol in urine over a 24-h period than controls, but less than 1% of the ingested dose was excreted. CONCLUSIONS: These results suggest that persistent diarrhoea in this population is associated with reduced bioavailability of retinol. Further work is required to determine the metabolic fate of therapeutic doses of retinol and to determine appropriate replacement strategies for HIV infected individuals.

Administration, Oral↗
PubMed2001

Interferon gamma induces enterocyte resistance against infection by the intracellular pathogen Cryptosporidium parvum.

BACKGROUND & AIMS: Interferon (IFN)-gamma plays an important role in the immunologic control of infection by the protozoan enteropathogen Cryptosporidium parvum. We tested the hypothesis that IFN-gamma may directly inhibit infection of enterocytes by this pathogen. METHODS: HT-29, Caco-2, and H4 human enterocyte cell lines were grown in monolayers and incubated with IFN-gamma before exposure with C. parvum. IFN-gamma receptor expression in the cell lines was determined by Western blot analysis. RESULTS: IFN-gamma inhibited C. parvum infection of both HT-29 and Caco-2 cells but not H4 cells. Response to IFN-gamma was related to the expression of the IFN-gamma receptor in the respective cell lines. The effect of IFN-gamma was partially reversed by inhibition of the JAK/STAT signaling pathway. IFN-gamma mediated its action by at least 2 mechanisms: (1) inhibition of parasite invasion and (2) by modification of intracellular Fe(2+) concentration. No role for tryptophan starvation or nitric oxide synthase activity was found. TNF-alpha and IL-1beta also had anti-C. parvum activity but had no synergistic effect with IFN-gamma. CONCLUSIONS: IFN-gamma directly induces enterocyte resistance against C. parvum infection; this observation may have important consequences for our understanding of the mucosal immune response to invasive pathogens.

Animals↗
PubMed2001

A prospective controlled trial of an ultrathin versus a conventional endoscope in unsedated upper gastrointestinal endoscopy.

BACKGROUND AND STUDY AIMS: Upper gastrointestinal endoscopy is performed without sedation in many countries. Unsedated patients experience more discomfort during endoscopy than sedated patients, but few studies have examined factors which could be modified to minimize discomfort during the procedure. We assessed the effect of endoscope diameter on patient discomfort during unsedated transoral gastroscopy. PATIENTS AND METHODS: A total of 322 patients attending for unsedated endoscopy were examined using an endoscope of diameter either 6.0 mm or 9.8 mm. Patients completed a two-part questionnaire assessing tolerance of the procedure and discomfort during it. RESULTS: There was failure to complete the initial unsedated endoscopy in three of 163 patients in the 6.0 mm group and 14 of 159 in the 9.8 mm group (P = 0.009). Patients in the 6.0 mm group reported less discomfort both during endoscope insertion (P < 0.0001) and during the remainder of the procedure (P < 0.0001). 14% of patients in the 6.0 mm group indicated that they would request sedation if a further endoscopy were necessary, compared with 31% in the 9.8 mm group (P = 0.0005). CONCLUSIONS: Ultrathin endoscopes may have a role in clinical practice if randomized comparative studies with standard-bore instruments confirm that they do not compromise diagnostic quality.

Adolescent↗
PubMed2001

Novel adaptation of brush cytology technique for short-term primary culture of squamous and Barrett's esophageal cells.

BACKGROUND: Esophageal disease research is impeded by a paucity of nonmalignant cell lines. Furthermore, culture of primary esophageal cells is difficult because of a lack of cell adhesion and contamination. The aim of this study was to develop a short-term culture method to facilitate cell physiologic studies by using primary esophageal cells. METHODS: By using a cytology brush, squamous and Barrett's epithelial cells were obtained from the esophagus of patients undergoing upper endoscopy. Cells were brushed onto chamber slides and allowed to adhere to the surface. Primary culture media was then added and cells were maintained at 37 degrees C for up to 72 hours. Cell yield and viability were calculated after trypan blue staining. For cell physiologic studies, cells were loaded with pH-sensitive dye BCECF-AM and intracellular pH measured on a dual excitation fluorescence microscope after an ammonium chloride prepulse. At the end of the physiologic experiments, cells were fixed in methanol and acetone and the cell type was verified with cytokeratin immunocytochemistry. RESULTS: Viable human esophageal cells were maintained in culture for up to 72 hours. The cells extruded trypan blue, and BCECF-AM was cleaved to BCECF by an intact cell membrane and permitted intracellular pH measurements. The epithelial cell origin of the cells was confirmed by cytokeratin staining. There was no contamination over the culture period and no overgrowth by lymphocytes or fibroblasts. CONCLUSIONS: This novel adaptation of brush cytology technique enables short-term culture of esophageal cells for in vitro studies. This rapid, simple primary culture technique is suitable for endoscopy and does not require the immediate, time-consuming laboratory techniques.

Barrett Esophagus↗
PubMed2001

Factors associated with tolerance to, and discomfort with, unsedated diagnostic gastroscopy.

BACKGROUND: Identification of patients likely to experience high levels of discomfort during unsedated gastroscopy would be useful as these patients could be prospectively targeted for sedation. We prospectively assessed patient and endoscopic variables in subjects attending for endoscopy in order to identify factors associated with patients' experience of the unsedated examination. METHODS: We studied 508 patients attending for routine diagnostic gastroscopy. Clinical and endoscopic data were collected and patients completed a two-part questionnaire assessing their anxiety with, and experience of, the procedure. RESULTS: Thirty-nine subjects failed to complete the initial unsedated endoscopy. Failure to tolerate endoscopy was associated with younger age (P = 0.002) and examination with a standard-bore (> or = 9.0 mm) endoscope (P = 0.004). High levels of patient discomfort during the procedure were associated with younger age (P < 0.001), high levels of pre-endoscopic anxiety (P < 0.001), high levels of pre-endoscopic discomfort due to throat spray (P = 0.02) and examination with a standard-bore endoscope (P < 0.001). Preference for sedation during future examinations was related to female gender (P = 0.02), young age (P = 0.02), high levels of apprehension (P < 0.001), the examining doctor (P = 0.002) and use of a standard-bore endoscope (P < 0.001). CONCLUSIONS: Discrete clinical characteristics and endoscopic variables are associated with patients' experience of unsedated endoscopy. Further work might result in an algorithm for identifying patients who would benefit from sedation prior to gastroscopy.

Age Factors↗
PubMed2001

Tropical enteropathy: a T-cell-mediated crypt hyperplastic enteropathy.

OBJECTIVE: Tropical enteropathy is widespread throughout the tropics, but its pathogenesis is unknown. T-cell activation has been demonstrated to result in enteropathy in vitro and in animal models, and occurs in untreated patients with coeliac disease. We have therefore examined the hypothesis that T-cell activation is important in the pathogenesis of tropical enteropathy. PATIENTS AND METHODS: Healthy black Zambian subjects were compared with black and white South Africans. Quantitative microscopy was conducted on distal duodenal biopsies. Mucosal T-cell activation was quantitated by dual colour immunofluorescence staining for CD3 plus CD69 or HLA-DR. Crypt proliferation was measured by direct counting of Feulgen-stained mitotic figures, and systemic immune activation by assay of serum tumour necrosis factor alpha (TNF-alpha). RESULTS: Villous height was reduced (P = 0.0004), crypt depth increased (P < 0.0001), and mitoses per crypt increased (P = 0.014) in black Zambians compared with black and white South Africans. Mucosal thickness was similar. Intraepithelial lymphocyte count was increased in the black groups compared with whites (P = 0.03). CD3+CD69+ (P = 0.0007) and CD3+HLA-DR+ (P < 0.0001) expression was increased in black Zambians compared with black and white South Africans. Serum TNF-alpha was similar in all groups. CONCLUSIONS: Tropical enteropathy is associated with mucosal T-cell activation and crypt hyperplasia. Tropical enteropathy occurs in the absence of malnutrition, diarrhoea or systemic illness.

Adult↗
PubMed2001

Helicobacter pylori pore-forming cytolysin orthologue TlyA possesses in vitro hemolytic activity and has a role in colonization of the gastric mucosa.

Hemolysins have been found to possess a variety of functions in bacteria, including a role in virulence. Helicobacter pylori demonstrates hemolytic activity when cultured on unlysed blood agar plates which is increased under iron-limiting conditions. However, the role of an H. pylori hemolysin in virulence is unclear. Scrutiny of the H. pylori 26695 genome sequence suggests the presence of at least two distinct hemolysins, HP1086 and HP1490, in this strain. Previous studies have shown that the in vitro hemolytic activity of H. pylori is reduced when it is coincubated with dextran 5000, suggesting the presence of a pore-forming cytolysin. HP1086 has homology to pore-forming cytolysins (TlyA) from other bacterial species, and the introduction of the cloned H. pylori tlyA gene into a nonhemolytic Escherichia coli strain conferred hemolytic activity. An H. pylori tlyA defined mutant showed reduced in vitro hemolytic activity, which appears to be due to pore formation, as the hemolytic activity of the wild-type strain is reduced to the same level as the tlyA mutant by the addition of dextran 5000. The mutant also showed reduced adhesion to human gastric adenocarcinoma cells and failed to colonize the gastric mucosa of mice. These data clearly suggest a role in virulence for H. pylori TlyA, contrary to the suggestion that hemolytic activity is an in vitro phenomenon for this pathogen.

Animals↗
PubMed2001

Delayed puberty and response to testosterone in a rat model of colitis.

Delayed puberty is a frequent complication of inflammatory bowel disease. The precise etiological mechanisms are not known. In this study, we wanted to determine the relative contribution of undernutrition and inflammation to delayed puberty and the effect of inflammation on the reproductive axis. Puberty was assessed in rats with 2,4,6-trinitrobenzenesulfonic acid induced-colitis, healthy controls, and animals pair fed to match the food intake of the colitic group. The response to testosterone administration was assessed in colitic rats. We found that induction of colitis was associated with hypophagia and reduced weight gain, and undernutrition in healthy females (i.e., pair fed) resulted in a delay in the onset (by 4.8 days, P < 0.001) and progression of puberty (normal estrous cycles in 42%, P = 0.04) compared with controls. However, puberty was further delayed in the colitic group (1.4 days after pair fed) with the absence of normal estrous cycling in all rats. In males, the onset of puberty was also delayed, and weights of accessory sex organs were reduced compared with pair-fed controls. Plasma testosterone concentrations were low, and gonadotropin concentrations were normal in colitic rats. Testosterone treatment normalized puberty in male rats with colitis. In conclusion, in rats with experimental colitis, inflammation appears to potentiate the effect of undernutrition on puberty. The weights of secondary sex organs and the onset of puberty were normalized by testosterone treatment.

Animals↗
PubMed2001

Role of hypothalamic neuropeptide Y and orexigenic peptides in anorexia associated with experimental colitis in the rat.

Neuropeptide Y (NPY) is thought to play a crucial role in the normal hypothalamic response to starvation. After a period of food restriction, increased release of NPY induces hunger and hyperphagia, and helps to restore body weight to its set point. Persistent anorexia in rats with experimental colitis implies failure of this adaptive feeding response. In vivo NPY release and regional hypothalamic NPY concentrations were measured in rats with trinitrobenzenesulphonic acid (TNBS)-induced colitis, healthy controls and animals pair-fed to match the food intake of the colitic group. Food intake in the colitic group was assessed after administration of NPY and two other potent orexigenic peptides: melanin-concentrating hormone (MCH) and hypocretin (orexin-A). Food intake was decreased by 30-80% below control values for 5 days in the colitic rats. In both the pair-fed and colitic groups, release of NPY in the paraventricular nucleus was significantly increased compared with free-feeding controls. Intraventricular or intrahypothalamic administration of NPY, MCH or hypocretin elicited a feeding response in healthy controls, but not in the colitic group. In summary, animals with TNBS-colitis and anorexia show an appropriate increase in hypothalamic NPYergic activity. However, the failure of NPY and other orexigenic peptides to increase feeding in the colitic group indicates suppression of feeding, either by inhibition of a common downstream hypothalamic neuronal pathway or by induction of one or more potent anorexigenic agents.

Adaptation, Physiological↗