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Biomedical subjects

N S Williams

Publications and source records attributed to N S Williams.

At least 55 records · Page 3Linked to original sources
PubMed1999

Sensory and autonomic neuropathy in patients with idiopathic slow-transit constipation.

BACKGROUND: Slow-transit constipation (STC) is a severe disorder of unknown aetiology, which may result from an autonomic or sensory neuropathy. This study aimed to investigate patients with STC for the presence of neural dysfunction, and relate the findings to other factors, including any familial associations. METHODS: Thirty-three patients with STC were studied using standard neurophysiological tests and a range of quantitative sensory and autonomic tests. The findings were compared with those of 20 matched control subjects and nine diabetic patients with gastrointestinal symptoms. RESULTS: Twenty of the 33 patients with STC gave a family history of constipation, including an affected identical twin and Hirschsprung's disease (n = 3). None had abnormalities on neurological examination or nerve conduction studies. Fifteen of the 33 patients had abnormalities on quantitative tests, including all six who required a colectomy. Eleven patients with STC had reduced axon-reflex sweating in the presence of normal sweat gland responses (P < 0.001, all patients with STC versus controls). Twelve patients with STC had small sensory fibre dysfunction, with significantly increased thermal thresholds (cool, P < 0.05; warm, P < 0.01); these included six of nine patients with STC and rectal hyposensation. There were similar findings on quantitative testing in diabetic patients. CONCLUSION: Quantitative tests in patients with STC provide evidence of a small fibre neuropathy. The high incidence of a positive family history, particularly a possible association with Hirschsprung's disease, suggests a genetic basis, which deserves further investigation.

Adolescent↗
PubMed1999

Comparative study of two sites of colonic conduit placement in the treatment of constipation due to rectal evacuatory disorders.

BACKGROUND: Chronic constipation may be treated by antegrade colonic irrigation via a colonic conduit. METHODS: Two alternative sites of colonic conduit construction were evaluated for their effect on the symptoms of 21 consecutive women with intractable constipation primarily due to rectal evacuatory disorders. The conduit was constructed in the sigmoid colon in the first 11 patients and in the transverse colon in the subsequent ten. Symptomatic outcome was evaluated clinically and by questionnaires, with a prospective quality of life assessment in the transverse group. RESULTS: During a median follow-up of 12 (range 6-60) months, reflux or stenosis necessitated revision or dilatation in six patients. Irrigation with a median of 1.3 (0.8-2.0) litres of water achieved evacuation in all patients. Improvements in abdominal pain and bloating were reported by seven of the ten patients in the transverse conduit group, but benefit was found in only three of 11 in the sigmoid group. There was no significant improvement in quality of life scores. In the medium term, seven patients retained a transverse conduit compared with three with a sigmoid conduit. CONCLUSION: The transverse colonic conduit offers better relief from the symptoms of constipation due to rectal evacuatory dysfunction than the sigmoid conduit.

Abdominal Pain↗
PubMed1999

Preliminary results of a multicentre trial of the electrically stimulated gracilis neoanal sphincter.

BACKGROUND: The electrically stimulated gracilis neoanal sphincter was initially developed to treat refractory incontinence. Good early results were reported from the two centres that pioneered the technique. The aim of this study was to assess the operation in a prospective multicentre setting. METHODS: The procedure was performed on 64 patients from seven centres worldwide and was performed in stages. All patients were evaluated clinically and manometrically before and after operation. RESULTS: There was a high incidence of infective and hardware-related complications. At a median of 10 months following closure of the defunctioning stoma 56 per cent had experienced a good functional result. The major functional problems comprised evacuatory difficulties experienced by 25 per cent. CONCLUSION: The technique is effective in treating otherwise refractory incontinence. It is, however, a complex procedure and the morbidity rate may be high, particularly during the learning curve, factors that necessitate careful patient selection. Presented to the Association of Surgeons of Great Britain and Ireland in Bournemouth, UK, April 1997 and the European Council of Coloproctology in Edinburgh, UK, June 1997; and published in abstract form as Br J Surg 1997; 88(Suppl): 39 and Int J Colorectal Dis 1997; 12: 144

Adolescent↗
PubMed1999

Treatment of rectal cancer--a critical update.

The treatment of rectal cancer still remains primarily surgical in nature. Techniques have evolved from complete extirpation of the rectum and anal canal which left the patient with a permanent colostomy, to sphincter-saving procedures. Effort is now concentrated on reducing local recurrence by combining total mesorectal excision with adjuvant radiotherapy and there is good evidence that both are effective. However, it is likely that only adjuvant chemotherapy will improve survival, and numerous studies are currently in progress to determine the best combination of drugs. In addition, attempts are being made to improve the functional results of sphincter-saving surgery, most notably by the addition of a colonic pouch to the procedure.

Chemotherapy, Adjuvant↗
PubMed1998

Development of self-recognition systems in natural killer cells.

Differentiation of NK cells is bone marrow dependent. Although all the factors necessary for NK differentiation are yet to be fully characterized, IL-15 has emerged as the most likely candidate that drives terminal differentiation of NK cells. Other cytokines are needed for the expansion and maintenance of the progenitor population. Although the in vivo role for IL-15 cannot be established without the generation of either IL-15 or IL-15R alpha deficient mice, in vitro data suggests that it is responsible for the generation of lytic, NK1.1+ cells from immature progenitors. So far, it has not been possible to obtain Ly-49+ cells from marrow or fetal-derived progenitor cells in vitro. Stromal cells along with cytokines may be necessary to induce expression of Ly-49 on NK1.1+ cells. Expression of the NK receptors seems to be a sequential process with expression of IL-2/15R beta on progenitor cells occurring first followed by the expression of NK1.1 and then probably Ly-49. The same sequence seems to hold true in vivo as well, Ly-49 surface expression on splenic NK1.1+ cells is first detected 4-6 days after birth, and the frequency of cells expressing Ly-49 receptors reaches adult levels by days 20-24. Despite the lack of expression of Ly-49 receptors by fetal NK1.1+ as well as bone marrow derived NK1.1+ cells, they are able to distinguish between MHC class Ihi and class Ilo targets. This suggests that these NK1.1+Ly-49- cells express non-Ly-49 class I receptors. Efforts in the future need to be focused on elements responsible for the expression of Ly49 on these NK1.1+ cells in order to establish an in vitro system in which establishment of the Ly-49 repertoire can be studied.

Animals↗
PubMed1998

Genetic detection of lymph node micrometastases in patients with colorectal cancer.

BACKGROUND: Undetected micrometastases represent the single most important cause of treatment failure in patients undergoing putatively curative resection for colorectal cancer because current staging techniques are unable to identify patients with minimal residual disease. METHODS: A highly sensitive reverse transcription-polymerase chain reaction technique has been used to amplify tissue-specific messenger RNA from lymph nodes classified as tumour-free using both conventional histopathology and immunohistochemistry. RESULTS: Four of 15 patients were restaged after genetic diagnosis of lymph node micrometastases, while in a further two additional positive nodes were detected. CONCLUSION: Sensitive genetic techniques that detect minimal residual disease merit further study, particularly as there is evidence that patients may benefit from adjuvant chemotherapy.

Adult↗
PubMed1998

Pelvic bioelectrical impedance measurements to detect rectal filling.

Anorectal sensory deficits are an important cause of defecatory disorders and are also a reason for evacuatory difficulties in patients undergoing total anorectal reconstruction. A method to detect rectal filling would be beneficial in such patients. We have investigated the feasibility of detecting rectal filling in vitro and in vivo by measuring changes in pelvic impedance. In vitro, a model of the pelvis was constructed using a cylindrical plastic tank filled with an electrolyte solution (conductivity 3 mS cm(-1)). Conductive Visking tubing representing the rectum was suspended in the tank and incrementally filled with artificial faeces. An impedance meter detected changes in voltage on rectal filling when an alternating current of 2 mA was passed at eight frequencies (4.8 to 612 kHz). In vivo, changes in pelvic bioelectrical impedance upon retrograde and antegrade rectal filling with artificial faeces were evaluated in three pigs, four electrodes being implanted in the pelvis. Impedance measurements accurately detected 'rectal' volume changes in vitro (n = 10, p < 0.0001; Kruskal Wallis), but not in vivo (n = 68, p = 0.48; Kruskal Wallis). This was probably due to extreme sensitivity of the detecting device to movement, a problem that needs to be resolved before this technique could be used in man.

Animals↗
PubMed1998

Natural killer cell differentiation: insights from knockout and transgenic mouse models and in vitro systems.

In the last few years, the routine development of knockout and transgenic mice and the ease with which rare progenitor populations can be isolated from hematopoietic organs and cultured in vitro has facilitated significant advances in understanding the lineage and development of natural killer (NK) cells. Fluorescence-activated cell sorter analyses have identified a common lymphoid progenitor capable of giving rise to NK, T, and B cells, confirming the lymphoid origin of NK cells. Knockout and transgenic mouse models have pointed to an absolutely critical role for signals sent through the interleukin (IL)-2/15 receptor beta (CD122) chain and common gamma (gamma c) chain for NK development. Such signals are likely relayed inside the cell by the tyrosine kinase Jak3, which associates with gamma c. Recently developed IL-15 and IL-15 receptor alpha knockout mice have pinpointed IL-15 as the mediator of this signal. Other mouse models have indicated an unexpected role for flt3 ligand in early NK-cell development as well as minor roles for stem cell factor and IL-7 in expanding NK-cell progenitor numbers. Finally, in vitro culture systems have proven useful in identifying the point in NK development at which each of these signals is critical.

Animals↗
PubMed1998

Routine versus selective school entrant medicals--a retrospective study on the Isle of Man.

A retrospective study was undertaken on the Isle of Man to see if there was a significant difference in the appropriateness of management of newly identified health problems between routine school entrant medical (routine SEM) and the recently introduced selective school entrant medical (selective SEM) and nurse school entrant assessment (nurse SEA). The study included advice and reassurance as an appropriate health outcome. In total, 602 records were reviewed and a chi-squared analysis undertaken. No significant difference in appropriate management was found between the two procedures when hearing, cardiovascular and testicular health problems were excluded. These health problems were excluded because the screening methods were not directly comparable and disadvantaged the school nurse. Future changes in nurse protocol were identified to reduce unnecessary referrals. The study supports the trend away from routine screens towards health promotion and ongoing surveillance by the school health service in partnership with parents, pupils and teachers as recommended in Reference 1.

Child, Preschool↗
PubMed1998

Anorectal reconstruction--restoring continence after abdominoperineal excision of the anorectum.

This article describes the technique of anal sphincter reconstruction using electrically stimulated graciloplasty. The results of recent published series of reconstruction after abdominoperineal excision are analyzed, and the modifications used to reduce complications are explored. Techniques of rectal reconstruction and methods of improving evacuation are also discussed. Techniques of reconstruction after high anorectal atresia as well as possible future developments in this field are considered. In the final section the possible qualitative benefits and the health economics of anorectal reconstruction are examined.

Abdomen↗
PubMed1997

Generation of lytic natural killer 1.1+, Ly-49- cells from multipotential murine bone marrow progenitors in a stroma-free culture: definition of cytokine requirements and developmental intermediates.

We have developed a stroma-free culture system in which mouse marrow or thymus cells, known to be enriched for lymphoid progenitors, can be driven to generate natural killer (NK) cells. Culture of lineage marker (Lin)-, c-kit+, Sca2+, interleukin (IL)-2/15Rbeta (CD122)- marrow cells in IL-6, IL-7, stem cell factor (SCF), and flt3 ligand (flt3-L) for 5-6 d followed by IL-15 alone for an additional 4-5 d expanded the starting population 30-40-fold and gave rise to a virtually pure population of NK1.1+, CD3- cells. Preculture in IL-6, IL-7, SCF, and flt3-L was necessary for inducing IL-15 responsiveness in the progenitors because the cells failed to significantly expand when cultured in IL-15 alone from the outset. Although culture of the sorted progenitors in IL-6, IL-7, SCF, and flt3-L for the entire 9-11-d culture period caused significant expansion, no lytic NK1.1+ cells were generated if IL-15 was not added, demonstrating a critical role for IL-15 in NK differentiation. Thus, two distinct populations of NK progenitors, IL-15 unresponsive and IL-15 responsive, have been defined. Similar results were obtained with Lin-, CD44+, CD25-, c-kit+ lymphoid progenitors obtained from adult thymus. The NK cells generated by this protocol lysed the NK-sensitive target YAC-1 and expressed markers of mature NK cells with the notable absence of Ly-49 major histocompatibility complex (MHC) receptors. However, despite the apparent lack of these inhibitory MHC receptors, the NK cells generated could distinguish MHC class I+ from class I- syngeneic targets, suggesting the existence of novel class I receptors.

Animals↗
PubMed1997

Perforin-dependent cytotoxic activity and lymphokine secretion by CD4+ T cells are regulated by CD8+ T cells.

Factors influencing the development of CD4+ T cell subpopulations with differing lymphokine profiles are well established. However, CD4+ cells can show both perforin- and Fas ligand-dependent cytotoxicity, and little is known about conditions favoring the development of these effector activities. We now report that CD8+ cells regulate the development of perforin-dependent cytotoxicity in CD4+ cells. CD4+ cells activated in either the presence or absence of CD8+ cells developed Fas ligand-dependent cytotoxic activity. However, CD4+ cells developed perforin-dependent cytotoxicity only in the absence of activated CD8+ cells. CD8+ cells also inhibited the development of IL-4-secreting CD4+ cells; however, there was no correlation between the expression of perforin-dependent cytotoxic activity and the ability to secrete IL-4, and perforin-dependent cytotoxic CD4+ cells represented only 10% of isolated clones. This suggests that the two characteristics are expressed in different CD4+ subsets and might be regulated by distinct effects of the CD8+ cells. In keeping with this, regulation of the lymphokine profile of CD4+ cells by CD8+ cells was consistent with mediation by IFN-gamma, but only when delivered at high concentrations requiring close proximity of the cells. In contrast, regulation of perforin-dependent cytotoxic activity of CD4+ cells by CD8+ cells seemed inconsistent with an IFN-gamma-dependent mechanism, suggesting either direct cell contact or close proximity to allow delivery of an unidentified soluble factor. The characteristics of perforin-dependent CD4+ CTL and their regulation by activated CD8+ cells suggest that they represent a previously unrecognized subpopulation that plays a defensive role when a CD8+ cell response is absent.

Animals↗
PubMed1997

Glial-derived neurotrophic factor in human adult and fetal intestine and in Hirschsprung's disease.

BACKGROUND & AIMS: Glial cell line-derived neurotrophic factor (GDNF) signals through the product of the ret proto-oncogene, which is known to be mutated in Hirschsprung's disease and other conditions with gut dysmotility. The aim of this study was to determine the presence of GDNF and its receptor component (RET) in human adult and developing intestine and to evaluate their distribution pattern in Hirschsprung's disease. METHODS: GDNF and RET were detected immunohistochemically, and GDNF was quantified by immunoassay in specimens of human adult and fetal colon and Hirschsprung's disease intestine. RESULTS: GDNF-like immunoreactivity was detected in all specimens. Immunostaining of GDNF was restricted to neural fiber-like structures across the gut wall and was similar to staining with markers of glia and Schwann cells. In contrast, RET immunoreactivity was found only in neural cell bodies. GDNF levels determined by immunoassay were higher in muscle than mucosal gut layers, and there was no difference between affected and unaffected segments of Hirschsprung's disease. CONCLUSIONS: GDNF is present in adult and fetal human gut, where it may play a neurotrophic role. Its staining pattern suggests that it is localized in glia or Schwann cells. There seems to be no difference of GDNF levels between affected and unaffected intestinal segments in Hirschsprung's disease.

Adult↗
PubMed1997

Zamifenacin (UK-76, 654) a potent gut M3 selective muscarinic antagonist, reduces colonic motor activity in patients with irritable bowel syndrome.

BACKGROUND: Zamifenacin is a new potent gut M3 selective muscarinic antagonist developed for possible use in irritable bowel syndrome. METHODS: In this multicentre, double-blind, parallel group, placebo-controlled study, the effect of a single dose of zamifenacin 10 mg or 40 mg on both fasting (30 min) and fed (60 min) colonic motor activity was assessed in 36 patients with irritable bowel syndrome (aged 25-68 years; 19 male). Colonic motility was recorded using a five-channel solid-state catheter introduced by colonoscopy to a depth of 35 cm in an unprepared colon. RESULTS: Zamifenacin 40 mg profoundly reduced colonic motility, particularly after the meal (P < 0.05). This was reflected by a significant reduction in the mean amplitude of contractions, number of contractions, percentage duration of contractions, activity index and the motility index (P < 0.05). A smaller reduction in all the motility parameters was obtained with 10 mg zamifenacin, but these changes were not statistically significant. Three patients each on placebo and zamifenacin reported side-effects, but these were mild and transient. CONCLUSION: A single 40 mg dose of zamifenacin significantly reduces colonic motility in irritable bowel syndrome patients without significant antimuscarinic effects. The results of this study confirm that the concept of developing selective antimuscarinic agents may be a promising approach to the treatment of irritable bowel syndrome. Not only would such compounds benefit from not having the usual side-effects of anticholinergics but they might also offer much more in the way of dose flexibility.

Adult↗
PubMed1997

The electrically stimulated gracilis neo-anal sphincter.

Many patients with incontinence gain no relief from their symptoms following traditional surgical treatment and by necessity resort to a stoma. A number of attempts have been made to replace damaged or excised sphincters using the gracilis muscle to fashion a neo-anal sphincter. The results of the published series using the technique of unstimulated graciloplasty for the treatment of anal incontinence and in total anorectal reconstruction are reviewed. The results of these series are conflicting. In an effort to improve on these results the electrically stimulated neo-anal sphincter has been developed. The rationale behind its development and its evolution are discussed. The efficacy of the procedure in treating patients with incontinence or as part of total anorectal reconstruction is assessed.

Adult↗