The development of Singapore nursing education system - challenges, opportunities and implications.

BACKGROUND: Singapore's nursing services and education need to keep pace with the ever-changing healthcare landscape and international trends in nursing capability development. AIMS: To examine the development of Singapore's nursing education and to propose recommendations for its future development. SOURCES OF EVIDENCE: This discussion paper examined journal articles, books and grey literature that documented the development of nursing education in Singapore. DISCUSSION: There are three main challenges and opportunities for nursing education in Singapore: (1) the establishment of registered nurse preparatory education at the baccalaureate level, (2) the expansion of master's programmes for clinical specialization and (3) the need to increase nursing faculties through the growth of doctoral education. CONCLUSION: Singapore's nursing education has made a significant progress in its development since the 1990s. To advance nursing education, individual nurses, local nursing associations and academic institutions should be empowered to develop its own clinical, education and research capabilities to meet future healthcare challenges. IMPLICATIONS FOR NURSING POLICY: Nurses should assume greater roles in determining their own professional and educational developments. Strategies to advance Singapore's nursing education include establishing a national body for regulating continuing nursing education and specialties certification, creating a greater diversity in academic offerings beyond baccalaureate programmes and building local nursing clinical and research capabilities within universities.

Prognostic significance of TP53 gene mutation in 995 cases of colorectal carcinoma. Influence of tumour site, stage, adjuvant chemotherapy and type of mutation.

Previous studies on the prognostic significance of TP53 gene alterations in colorectal cancer (CRC) have led to conflicting results. The present study investigated the prognostic significance of TP53 gene mutation in a very large series of 995 Dukes' B and C CRC patients, the majority of whom did not receive chemotherapy. Mutations were found in 385 (39%) cases and were not associated with tumour stage, histological grade, patient age or sex. Significantly more mutations were found in tumours from the left-sided colon compared with those from the right side (43% versus 34%, P=0.006). TP53 gene mutation had no prognostic value in the overall series or in different site or stage subgroups. None of the different types of TP53 gene mutation showed prognostic value. A trend for association with worse survival was observed in the patient subgroup that received adjuvant chemotherapy (Hazard Ratio (HR) 1.4, 95% confidence interval (CI) 0.89-2.21, P=0.15). These results indicate that mutation of the TP53 gene is not a useful prognostic marker for CRC patients who do not receive adjuvant chemotherapy. Further study is required to determine whether different types of TP53 mutation might be of value in predicting the response of CRC patients to chemotherapy.

Prostate tumours from an Asian population: examination of bax, bcl-2, p53 and ras and identification of bax as a prognostic marker.

Molecular studies have suggested that ethnicity may play a significant role in prostate tumorigenesis, but no information exists for groups other than Caucasian or Japanese patients. We examined 62 archival samples of prostate tumours from Asians of non-Japanese origin for the over-expression of p53, for the possible presence of mutated ras genes, for the overexpression of the bcl-2 and bax proteins, as well as directly for the presence of apoptotic cells by the TUNEL methodology. Gene lesions of both ras (0%) and p53 (3%) were rare. While bcl-2 expression was not observed in any sample, bax expression was noted in 76% of samples and was associated with a significantly worse patient prognosis both overall (P< 0.005) and specifically in Chinese patients (P< 0.02). Apoptotic cells were found in 61% of samples, and were significantly associated with the presence of bax expression (P = 0.002), but not patient survival. These results suggest that prostate tumours from non-Japanese Asians are genetically distinct from prostate tumour found in both Japanese and Caucasian patients, and that treatment modalities may need to be tailored for specific population groups.

Apoptosis and apoptosis related gene expression in normal conjunctiva and pterygium.

BACKGROUND: Pterygium is a relatively common eye disease in the tropics whose aetiology and pathogenesis remain uncertain. As such, interest has focused on understanding the underlying mechanism of pterygia development. METHODS: 15 specimens of pterygia from 15 eyes were examined, together with normal conjunctival tissue from the same eyes for the pattern of gene expression of genes associated with the induction or repression of apoptosis (p53, bcl-2, and bax). In addition, the samples directly for apoptotic cells were examined by the terminal deoxynucleotide transferase (TdT) mediated nick end labelling (TUNEL) methodology. RESULTS: In pterygia specimens apoptotic cells were found mainly confined to the basal layer of cells of the epithelial layer, situated immediately adjacent to the fibrovascular support layer. These cells were shown to express significant levels of p53 and bax, as well as the apoptosis inhibiting protein bcl-2. In contrast, normal conjunctival specimens displayed no bcl-2 expression and apoptotic cells were seen throughout the entire width of the epithelial layer, coupled with high levels of bax expression. CONCLUSION: These results support a model whereby pterygia development is a result of disruption of the normal process of apoptosis occurring in the conjunctiva.

Young Investigator's Award: induction of apoptosis following traumatic head injury in humans.

Apoptosis or programmed cell death plays an important role in many developmental and pathological processes of the central nervous system. In head injury, apoptosis has been recently implicated in many studies on animal brain samples the phenomenon of apoptotic gene expression (bax and bcl-2). Twenty specimens of contused brain tissue (temporal and frontal lobe) from 20 patients who underwent emergency craniotomy and removal of mass lesions were obtained from May to October 1997. The samples collected were immediately snap frozen in liquid nitrogen and stored at -80 degrees C. Immunohistochemical analysis was performed to detect the expression of bcl-2, bax and p53 using standard avidin-biotin complex second antibody conjugate methodology utilising commercially available primary and secondary antibodies. The average age of cohort was 46.24 +/- 22.17 years, the average Glasgow Coma Scale on admission was 9.19 +/- 4.72, and the average duration from injury to collection of the sample was 20.62 +/- 40.57 hours. There was documented hypoxia and hypotension seen in 5 of the 20 patients (25%). Significant levels of bax protein expression were noted in all samples, and p53 expression in 30% of samples. No bcl-2 expression was observed. Our study showed that for the first time the strong expression of the pro-apoptotic gene (bax) and low levels of the anti-apoptotic gene (bcl-2), thus implicating the mechanism of apoptosis in brain injury following trauma. The use of agents to inhibit apoptosis may be beneficial in head injury patients.

HIT family genes: FHIT but not PKCI-1/HINT produces altered transcripts in colorectal cancer.

Forty-five colorectal adenocarcinomas were examined for alterations in the HIT family genes FHIT and PKCI-1/HINT by a combination of reverse transcriptase polymerase chain reaction and DNA sequencing. In all cases a single transcript corresponding to the reported sequence was detected using primers specific for the PKCI-1/HINT gene. In contrast multiple transcripts were detected using primers specific for the FHIT gene transcript. 6% (3/45) of tumours evinced no detectable expression of any FHIT transcript and a further 12% (6/45) produced only the normal full length transcripts. Ninety-six aberrant transcripts were characterized from the remaining tumours. Deviations from the normal full length sequence characterized included deletions, insertions of novel sequences, a point mutation as well as the usage of a putative alternate splice site in exon 10. Message variants were detected with approximately equal frequency in all tumour stages with the exception that templates with insertions were found solely in Dukes' stage B tumours (P < 0.001). With the exception of the putative alternate splice site, aberrant transcripts were not detected in matched normal mucosa. These results suggest that members of the HIT family of genes are only selectively involved in tumorigenesis and that perturbation of FHIT gene expression is an early event in colorectal tumorigenesis.

c-Ki-ras mutations in colorectal adenocarcinomas from a country with a rapidly changing colorectal cancer incidence.

We have examined the incidence of mutation of the c-Ki-ras proto-oncogene in colorectal adenocarcinomas from two different time periods, namely 1962-1966 and 1994-1996. The first cohort of samples consisted of formalin-fixed, archival paraffin block and represent the oldest colorectal cancer samples for which ras mutation has been examined, while the second cohort of tumours were fresh, flash-frozen samples representative of genetic events occurring in contemporary times. Analysis of mutation status was undertaken by a mismatch-specific oligonucleotide hybridization analysis of exon 1 of the c-Ki-ras proto-oncogene after amplification by the polymerase chain reaction. Mutations in codon 12 or 13 of c-Ki-ras were detected in 28% (14/50) of contemporary samples, a figure consistent with locally established mutation rates. In contrast no mutation was detected in any of the 18 samples from the earlier period, a result that is statistically significant (P = 0.007). Age-standardized rates of colorectal cancer in Singapore have seen a marked increase over the last 30 years, and for the first time we have shown that such an increase in colorectal cancer is associated, at least in part with an increase in incidence of a specific mutagenic change.

p53 point mutation and survival in colorectal cancer patients: effect of disease dissemination and tumour location.

The relationship between p53 point mutation and patient survival was examined in 328 colorectal cancer patients. Point mutation was detected in 51% (166/328) of cases and was associated with a poorer prognosis in univariate and multivariate analysis. However, subcohort analysis showed that this relationship was restricted to patients with lymphatic dissemination, patients without evident distant metastatic lesions at the time of presentation and in tumours confined to the distal colorectum. These results suggest that the utility of p53 point mutation as a specific, patient based prognostic marker may be restricted to certain classes of patients.

Abnormal expression of the p53 tumor suppressor gene in the conjunctiva of patients with pterygium.

PURPOSE: To determine whether pterygium is a disorder of abnormal growth by examining the expression of the p53 gene in the conjunctiva of patients with pterygium. METHODS: Immunostaining for abnormal expression of p53 was performed using mouse monoclonal antibody to human p53, pAb 240, on six eyes with primary pterygium and two eyes with recurrent pterygium. RESULTS: In three of the eight eyes with pterygium, specimens were positive for abnormal expression in the epithelium of the pterygium and in the superior bulbar conjunctiva. CONCLUSION: Abnormal p53 expression in the epithelium of primary and recurrent pterygium specimens suggests that pterygium is a growth disorder rather than a degeneration.

CMV colitis masquerading as colon cancer--an unusual presentation of acquired immunodeficiency syndrome.

We present a case-report of a patient with a typical history and a barium enema study diagnostic of right-sided colonic cancer. Laparotomy and right hemicolectomy was carried out. Histological examination revealed Cytomegalovirus (CMV) colitis and the patient was subsequently tested positive for Human immunodeficiency Virus (HIV). Gastrointestinal symptoms are common in patients with Acquired Immune Deficiency Syndrome (AIDS) and up to 10% of all AIDS patients have CMV colitis. The diagnostic criteria for CMV colitis is reviewed. AIDS is likely to become more common and we stress the awareness of this condition as well as the need for preoperative colonoscopy and histological diagnosis in patients with radiological diagnosis of colorectal carcinoma.

Surgery for inflammatory bowel disease in Singapore.

Inflammatory bowel disease is uncommon in Asians and reports of surgery in these populations are rare. Eighty-two patients with inflammatory bowel disease were seen in the Department of Colorectal Surgery over a five-year period (1989-1994). Twenty-three patients underwent surgery for their disease. There were 12 males and 11 females with 16 Chinese, 4 Indians and 3 Malays. Twelve had Crohn's disease and 11, ulcerative colitis. The majority of patients with Crohn's disease had emergency surgery for bleeding, perforation, abdominal masses and intestinal fistulae. Fifty percent of these had the diagnosis made intraoperatively or post-operatively. Surgery for ulcerative colitis was indicated because of multiple relapses, non-response to medical treatment, side effects of therapy or malignant change. The median age at surgery of patients with Crohn's disease and ulcerative colitis was 39 years (range 24-84) and 40 (range 18-60) respectively. The median follow-up was 22.4 months (range 9-50). The results of surgical therapy in these patients show that surgery when indicated can be done with minimum morbidity and mortality.

Prognostic significance of p53 overexpression and mutation in colorectal adenocarcinomas.

The p53 tumour-suppressor gene is found altered in the majority of colorectal cancers. Lesions include allelic loss, mutation of the gene and overexpression of the p53 protein. All of these lesions have been analysed for prognostic significance, and whereas both mutation and allelic loss have been shown to be reasonably useful markers of prognosis, the utility of overexpression of the p53 protein is more ambiguous. Given that many authors use p53 overexpression as a marker for point mutation this issue is of some importance. We have therefore examined 100 colorectal carcinomas for mutation of the p53 gene, as well as overexpression of the p53 protein. Results show that whereas mutation of the p53 gene is associated with p53 overexpression, the degree of association depends, at least in part, upon the particular antibody used. Moreover, although mutation of the p53 gene does provide prognostic information, overexpression of the p53 protein, as detected with two antibodies, does not. These results suggest that immunohistochemistry is not a suitable alternative to direct detection of mutation in assessing prognosis in colorectal cancer patients.

The investigation of chronic constipation for surgical management.

AIMS: This study was conducted to ascertain the incidence of patients requiring surgery for intractible constipation. We also aimed to determine the anorectal physiology findings which influenced the surgery, and the outcome of surgical intervention. METHODS: A prospective study was done on 217 patients (34 men, 183 women; mean age 59 years [SD 17.7]) managed in a tertiary referral centre. Physiological tests consisting of transit marker studies, anal manometry, electromyography (EMG) and synchronised mano-myo-cinedefaecography (SMC), were then performed where appropriate. Surgical management was based on the results of these investigations. The mean follow-up was 19.6 months (SD 9.3). RESULTS: Eighteen patients (8.3 percent) underwent surgery: 2 for Hirschsprung's disease, 8 for colonic inertia (CI) and 8 for obstructed defaecation (OD). CI patients were younger than the OD patients (p = 0.03). Transit marker studies were abnormal but manometry was not different from the OD patients. The latter were identified on SMC to have rectoceles, sigmoidocele or rectal intussusception. The stool frequency significantly improved after surgery (before = 1.9 bowel motions a week [SD 0.9], after = 8.8 bowel motions a week [SD 1.2]; p = 0.003). There were no complications. CONCLUSIONS: A small but significant proportion of constipation patients require surgery. Good results are obtainable when surgery is directed by the findings of anorectal physiology investigations.

Overexpression of the c-myc proto-oncogene in colorectal carcinoma is associated with a reduced mortality that is abrogated by point mutation of the p53 tumor suppressor gene.

The survival of 119 colorectal cancer patients was analyzed in the light of the overexpression status of the c-myc proto-oncogene mRNA and the point mutation status of the p53 tumor suppressor gene in the primary adenocarcinoma. The presence of >3 fold overexpression of c-myc mRNA in the primary tumor was found to be associated with a better prognosis than patients who evinced no overexpression (P = 0.02, log rank analysis). Point mutation of the p53 tumor suppressor gene was found to be associated with a poorer patient prognosis (P = 0.007, log rank analysis). Endogenous levels of c-myc and point mutation of p53 both contributed independently toward a poorer patient prognosis in Cox regression modeling. The better prognosis seen in patients who overexpress c-myc was offset when c-myc overexpression was coupled with a point mutated p53 gene. These results suggest that in colorectal adenocarcinoma c-myc deregulation leads to increased apoptotic death, but that this response may be modulated by a more downstream event such as point mutation of the p53 gene.

Clinical and physiologic effects of biofeedback in outlet obstruction constipation.

PURPOSE: We report the results of biofeedback (BF) on patients with outlet obstruction defecation (OOC), including those with and without measurable paradoxical puborectalis contractions (PP). Clinical and anorectal physiologic parameters (ARP) were assessed one week before and after a standardized course of BF. METHODS: Sixty-two consecutive patients (24 men, 38 women; mean age, 48 (standard error of the mean, 2.3) years) were recruited. All had persistent constipation despite six weeks of dietary fiber supplements. Colonic inertia was excluded by transit marker studies. Defecating proctography excluded anatomic abnormalities causing outlet obstruction. Patients underwent four outpatient sessions of biofeedback, each session lasting one hour. RESULTS: After BF, 56 patients (90.3 percent) were subjectively improved. Frequency of spontaneous bowel movements were significantly increased (P = 0.003). Frequency of laxative-induced (P = 0.004) and enema-induced (P = 0.005) stools were reduced. Anal resting (P = 0.04) and squeeze (P = 0.002) pressures were increased. Number of patients with PP was reduced from 40 to 31 (P = 0.004). Presence of PP did not affect response to BF. There were no differences in ARP between the 56 patients who improved and the 6 who did not. There were no side effects or clinical regressions after a mean follow-up of 14.9 (standard error of the means, 0.9) months. CONCLUSIONS: BF effectively treated OOC in 90.3 percent, regardless of PP. Anal pressures were increased, and PP was decreased.

C-KI-RAS activation and the biological behaviour of proximal and distal colonic adenocarcinomas.

One hundred and forty colonic adenocarcinomas originating on the left side of the colorectum and 70 colorectal carcinomas originating on right side of the colorectum were examined for activating mutations of codons 12 and 13 of the C-KI-RAS proto-oncogene. Rates of mutation were significantly different (right colon 43%, 30/70 versus left colon 23%, 32/140; P = 0.0025). Adenocarcinomas from the left side of the colorectum showed a significant association between C-KI-RAS activation and tumour progression, including the presence of distant organ metastasis at the time of surgery (P = 0.0039), and during patient follow-up (P = 0.00027), whereas those from the right of the colorectum did not (P = 0.4 and P = 0.5, respectively). Mutation of the C-KI-RAS proto-oncogene was found to be associated with a significantly poorer patient prognosis on the left of the colorectum (P = 0.0001 by log rank analysis of Kaplan-Meier plots) but not on the right (P = 0.7). These results demonstrate that, not only is the timing and frequency of C-KI-RAS activation different between carcinomas originating on the left or right of the colorectum, but also that the biological consequences of such mutations may differ.

Bowel function survey after segmental colorectal resections.

PURPOSE: Long-term bowel function after right hemicolectomy (RHC), extended right hemicolectomy (ERHC), left hemicolectomy (LHC), sigmoid colectomy (SC), and anterior resection (AR) was evaluated. METHOD: Three hundred fifteen patients (52.3 percent) replied to a questionnaire on stool frequency, fecal continence, and defecation problems. All patients had undergone surgery at least one year before questionnaire was sent to them. Patients with anastomotic leaks and recurrences were excluded. RESULTS: Stool frequency was one to two bowel movements per day in 78 percent of patients after RHC, 75 percent after ERHC, 57.6 percent after LHC, 64.3 percent after SC, and only 44.8 percent after AR (P = 0.01). Continence affected lifestyle in 32 percent of patients after AR, but affected only up to 11.5 percent of patients who had had more proximal resections (P = 0.001). Defecation problems occurred in less than 15.4 percent after RHC, ERHC, and LHC but were encountered more frequently after SC (25 percent) and AR (28.4 percent; P = 0.009). CONCLUSIONS: Problems with postoperative bowel function were appreciably more common after SC and AR.

p53 and prognosis in colorectal cancer.

The p53 tumour suppressor gene is found altered in the majority of colorectal adenocarcinomas. While these changes are believed to reflect underlying mechanisms of tumour development and progression, it is becoming increasingly clear that such changes may also reflect the macroscopic biological behaviour of the course of the disease. Knowledge of the p53 tumour suppressor gene status may therefore provide important prognostic information. This review examines some of the data that are beginning to show that p53 tumour suppressor gene status may be an important prognostic indicator.