Ninety-one healthy subjects (51 women; age range 16-85 years) were studied prospectively to determine the effect of age, sex and parity on anorectal function. Maximum resting pressure, voluntary contraction pressure, rectal sensation to distension, rectal and mid-anal electrosensitivity, perineal descent, pudendal nerve terminal motor latency and fibre density of the external and sphincter were measured. Sex influenced mean(s.d.) voluntary contraction pressure (148(56) versus 95(43) cmH2O for men versus women, P < 0.0001), perineal descent on straining (1.0(0.5) versus 1.3(0.4) cm, P = 0.02) and fibre density (1.43(0.14) versus 1.52(0.15), P = 0.02). Age influenced resting pressure (r = -0.43, P = 0.0001), perineal position at rest (r = -0.55, P < or = 0.0001), mid-anal electrosensitivity (r = 0.42, P = 0.0001) and rectal electrosensitivity (r = 0.54, P < 0.0001). Parity affected mean(s.d.) voluntary contraction pressure (105(53) versus 75(20) cmH2O for nulliparous versus parous women, P = 0.04) and mid-anal electrosensitivity (5.3(2.3) versus 4.5(2.3) mA, P = 0.02). Increasing age leads to perineal descent at rest, slowed pudendal nerve conduction, a fall in resting anal pressure and decreased anorectal sensory function. Women have a lower and squeeze pressure, greater perineal descent, longer pudendal nerve terminal motor latency and a greater muscle fibre density than men. Parity leads only to lower squeeze pressure.

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Urinary dysfunction is common in cases of multiple sclerosis (MS). The close proximity of those neural pathways which control the bladder to those which control anorectal function might be expected to lead to a high coexistence of bladder and bowel symptoms. Seventy-seven consecutive patients with clinically definite MS attending a uroneurology clinic were interviewed about their bowel function. All patients had clinical evidence of spinal cord disease with varying degrees of impaired mobility and sufficiently severe disturbance of bladder control to seek medical advice. Thirty-six per cent of these patients had constipation. Twenty per cent had "current incontinence", although another 30% had had at least one episode of faecal incontinence more than 3 months previously. Some patients had both constipation and faecal incontinence. A total of 52% currently had at least one bowel symptom. The pattern of bowel symptoms did not correlate with the pattern of urinary disturbance, or the duration of MS, or the degree of disability. Bowel symptoms are common in patients with MS, but even in those with urinary dysfunction are not universal. Whereas bladder dysfunction in MS is clearly related to spinal cord disease, the neurological basis for the bowel dysfunction is less clear.

The present study investigated the activity and cellular localization of individual isoenzymes of nitric oxide synthase (NOS) using immunohistochemistry and the [3H]citrulline assay in normal colorectal epithelia and neoplastic tissue. Intracellular localization of isoenzymes of NOS was detectable by immunohistochemistry in normal epithelial cells. Colorectal adenocarcinomas had a marked reduction of both Inducible NOS (iNOS) and constitutive NOS (cNOS) expression. Expression of iNOS was completely absent in tumour cells (P < 0.0001), while cNOS was reduced in 66% and absent in 34% of tumours studied when compared with controls (P < 0.0001). NOS activity using the [3H]citrulline assay was detectable in normal epithelium and was found to be reduced in tumours (P < 0.001). In addition, colonic adenomas had reduced INOS but not cNOS expression when compared with controls (P < 0.003 and P = 0.39 respectively). We conclude that NOS is present and active within the epithelium of the normal colon, with localization of the individual isoenzymes. Furthermore, there was loss of activity and expression of individual isoenzymes in colonic neoplasms.

Neoadjuvant endocrine therapy has been increasingly employed in clinical practice to improve surgical options for postmenopausal women with bulky hormone receptor-positive breast cancer. Recent studies indicate that tumour response in this setting may predict long-term outcome of patients on adjuvant endocrine therapy, which argues for its broader application in treating hormone receptor-positive disease. From the research perspective, neoadjuvant endocrine therapy provides a unique opportunity for studies of endocrine responsiveness and the development of novel therapeutic agents.

The expression of nitric oxide synthase (NOS) was studied by NAD(P)H diaphorase histochemical localization method in (i) individual cells of the normal colonic mucosa (n = 13) which served as control, (ii) colonic polyps (n = 14), (iii) colonic carcinoma (n = 20) and (iv) peritumoral mucosa (2 and 5 or 10 cm away from the tumor). Four of the tumor specimens had normal epithelium adjacent to the cancer, which thus served as an internal control. The expression of NOS activity in colon cancer was significantly reduced as compared to the control group of individuals (P < 0.004); undetectable in 25%, diminished in 45%, normal in 30%. On comparing the expression in normal mucosa and polyps there was a significant reduction of the expression in polyps (P < 0.027); undetectable in 14%, reduced in 35%, normal in 51%. When compared to the peritumoral mucosa at 2 and 10 cm the tumor showed a significant reduction in expression of NOS activity (P < 0.001 and P < 0.0001 respectively). There was no significant difference seen in the expression at 2 and 10 cm (P = 0.329). The peritumoral mucosa at a distance of 2 cm away from the tumor when compared to the control mucosa showed no significant difference (P = 1.000), although there is a tendency to a high normal expression of NOS activity in the mucosa at a distance of 2 cm. Similarly, there was no significant difference between the control mucosa and the peritumoral mucosa obtained at a distance of 10 cm (P = 0.383). The expression of NOS activity in all tissues examined was abolished by preincubation of tissue with the selective NOS inhibitor L-NMMA but not with D-NMMA. Our data showed extensive and significant reduction as identified by the NAD(P)H diaphorase method in the expression of NOS activity, thereby reflecting the activity of nitric oxide in colon cancer and colonic polyps. The generalized suppression of this activity, which precedes the onset of overt neoplasia, may be an important event in colon carcinogenesis. This aberrant expression could also be compatible with the selective advantage to either tumor promotion and metastatic progression or to tumoricidal activity.

Objective-To study the disturbed anorectal physiology associated with constipation in multiple sclerosis.

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