Biomedical subjects

P E O'Brien

Publications and source records attributed to P E O'Brien.

At least 19 recordsLinked to original sources

PubMed2006

Changes in fat-free mass during significant weight loss: a systematic review.

OBJECTIVE: To identify the proportion of weight lost as fat-free mass (FFM) by various weight loss interventions. METHODS: Medline and Embase were systematically searched for reliable measurements of FFM before and after weight loss of >10 kg and eligible data were pooled. In a fixed effect model of % FFM loss/weight loss (%FFML), linear regression analysis was used to determine the influence of degree of caloric restriction, exercise, magnitude of weight loss, initial body mass index (BMI) and type of surgery. RESULTS: Data were included from 26 cohorts treated with dietary and behavioral interventions and 29 cohorts of bariatric surgery patients. The degree of caloric restriction was positively associated with %FFML (r (2)=0.31, P=0.006) and in three randomized controlled trials exercise was shown to decrease %FFML. Compared with laparoscopic adjustable gastric banding (LAGB), biliopancreatic diversion (BPD) and roux en Y gastric bypass (RYGB) caused greater log(e) (natural log) %FFML (r (2)=0.453, P<0.001). Differences in log(e) %FFML between surgical procedures were independent of initial BMI and magnitude of weight loss. CONCLUSIONS: The degree of caloric restriction, exercise and rate of weight loss influence the proportion of weight lost as FFM after non-surgical interventions. For surgical interventions, BPD and RYGB result in greater %FFML than LAGB.

Absorptiometry, Photon↗

PubMed2005

Polysomnography before and after weight loss in obese patients with severe sleep apnea.

OBJECTIVE: While obstructive sleep apnea (OSA) is strongly related to obesity, few studies have examined polysomnographic (PSG) changes with major weight loss. We examined the effect of weight loss following laparoscopic adjustable gastric banding (LAGB) on the PSG changes in patients with severe OSA. In addition, we studied daytime sleepiness, the metabolic syndrome and quality of life (QOL). METHODS: A prospective study was conducted of 25 severely obese patients (17 men, eight women) with paired diagnostic PSG, biochemical and questionnaire studies, the first prior to LAGB and the second at least 1 y later. Subjects with a baseline apnea-hypopnea index (AHI) >25/h were included. RESULTS: Subject baseline age was 44.7 y, weight 154 kg and body mass index 52.7 kg/m(2). The second PSG study was conducted 17.7+/-10 (range 12-42) months after surgery and mean percentage of excess loss and weight loss were 50.1+/-15% (range 24-80%) and 44.9+/-22 kg (range 18-103 kg), respectively. There was a significant fall in AHI from 61.6+/-34 to 13.4+/-13, improved sleep architecture with increased REM and stage III and IV sleep, daytime sleepiness, as measured by Epworth Sleepiness Scale, of 13+/-7.0 to 3.8+/-3.0, and fewer patients requiring nasal continuous positive airways pressure (CPAP). There were also major improvements in the metabolic syndrome, QOL, body image and fewer symptoms of depression (P<0.05 for all). CONCLUSION: Weight loss provides major improvement or resolution of OSA and CPAP requirements. It also reduces daytime sleepiness, and improves the metabolic syndrome and QOL. LAGB placement should be considered a broadly effective therapy for sleep apnea in the severely obese patient.

Adult↗

PubMed2003

Body composition changes following laparoscopic gastric banding for morbid obesity.

Most reports of outcome following obesity surgery report weight and co-morbidity changes only. We studied body composition changes in 17 adult patients (15 F, 2 M, age 43+/-2 years, range 28-58 years), with morbid obesity (initial BMI 40.4+/-4.9 kg/m(2), range 34.7-48.8) who were managed surgically by laparoscopically inserting an adjustable gastric band. Body composition was studied before and after surgery (mean interval of 909+/-51 days, range 441-1155 days) using anthropometry (abdominal circumference, AC, sum of four skinfold thicknesses, SFSUM), whole-body potassium counting (TBK), in vivo neutron activation analysis total body nitrogen (TBProtein) and whole-body dual-energy ray absorptiometry (total body percent fat TBF%, and total body bone mineral density TBBMD). Weight loss over the study period was 23.4+/-2.5 kg. ( p<0.0003) with an AC reduction of 20.0+/-4.5 cm ( p<0.008). Both SFSUM and TBF% were significantly reduced ( p<0.02 and p<0.0005 respectively). Both TBK and TBProtein after normalization for sex and height, were significantly ( p<0.0054 and p<0.001 respectively) reduced, but the ratio of loss of fat mass to fat-free mass, at 4.4:1 was usual for weight loss, and there was no significant changes in the ratio of potassium to protein. TBBMD, after normalization relative to a young same sex adult, was not significantly changed. In this group of patients, most of the substantial weight loss over a 2- to 3-year period was due to loss of fat mass, with relatively less reduction in the components of fat-free mass. Adjustable laparoscopic gastric banding induces fat loss without significant other deleterious effects on body composition.

Absorptiometry, Photon↗

PubMed2003

Improvements in insulin sensitivity and beta-cell function (HOMA) with weight loss in the severely obese. Homeostatic model assessment.

AIMS: To examine the effect of weight loss on insulin sensitivity and beta-cell function in severely obese subjects of varying glycaemic control. PATIENTS AND METHODS: Subjects were 254 (F:M 209:45) patients having adjustable gastric banding for severe obesity, with paired biochemical data from before operation and at 1-year follow up. The homeostatic model assessment method was used to calculate insulin sensitivity (HOMA%S) and beta-cell function (HOMA%B). Subjects were grouped by diabetic status and by pre-weight loss HbA1c. RESULTS: Initial mean (sd) weight and body mass index were 128 (26) kg and 46.2 (7.7) kg/m2, respectively, and at 1-year were 101 (22) kg and 36.4 (6.7) kg/m2. The percentage of excess weight lost (%EWL) was 44.3 (14)%. HOMA%S improved from 37.5 (16)% presurgery to 62 (25)% (P < 0.001). %EWL was the only predictor of HOMA%S improvement (r = 0.28, P < 0.001). Subjects with normal fasting glucose, impaired fasting glucose and Type 2 diabetes had a fall, no change and increase in HOMA%B, respectively. The improvement in HOMA%B in subjects with diabetes (n = 39) was inversely related to the time with diabetes (r = -0.36, P = 0.02). In non-diabetic subjects the HOMA%S-HOMA%B relationship was favourably altered with weight loss, so that for any given HOMA%S there was an increase in HOMA%B (f = 11.8, P = 0.001). This improvement in HOMA%B was positively related to %EWL (r = 0.25, P = 0.019). DISCUSSION: There are beneficial changes in both insulin sensitivity and beta-cell function with weight loss. Modern laparoscopic obesity surgery may have an important early role in the management of Type 2 diabetes in obese subjects.

Adult↗

PubMed2002

Reduced plasma homocysteine in obese red wine consumers: a potential contributor to reduced cardiovascular risk status.

BACKGROUND: Moderate alcohol consumption is associated with improved vascular risk profile and decreased mortality in the middle aged. An elevated homocysteine concentration is an independent risk factor for cardiovascular disease. OBJECTIVE: To examine the relationship between alcohol consumption and homocysteine concentrations in severely obese patients (body mass index (BMI)>35). DESIGN: A careful alcohol history was obtained from 350 (male:female 1:5) consecutive patients as part of preoperative assessment for surgical treatment of obesity. Data were obtained concerning amount, frequency, timing and type of alcohol consumption. Fasting homocysteine, serum folate and vitamin B(12) concentrations were measured. Differences between groups were assessed using Student t-test, and ANOVA. Linear regression was used to assess factors influencing homocysteine concentration. RESULTS: There is a U-shaped relationship between alcohol consumption and homocysteine concentrations, with light to moderate consumption being associated with lower concentrations. Those consuming <100 g/week (n=165) of alcohol had geometric mean (95% CI of mean) serum homocysteine concentrations of 8.5 (8.2-8.9) micromol/l compared with 9.5 (9.1-9.9) micromol/l for non or rare consumers (n=153; P=0.001). The lower concentrations of homocysteine in regular consumers were associated with higher folate concentrations of 9.4 (8.6-10.2) ng/ml when compared with non-consumers 7.5 (7.1-7.8) ng/ml (P=0.001). Red wine consumers (n=42) had lower fasting concentrations of homocysteine 7.8 (7.5-8.1) micromol/l compared with 153 non-consumers 9.4 (9.0-9.8) micromol/l (P<0.001), 82 beer and spirit consumers 9.0 (8.4-9.7) micromol/l (P=0.005) and 73 white wine consumers 8.8 (8.2-9.4 micromol/l (P=0.013). Red wine consumption was an independent predictor for lower homocysteine concentrations. CONCLUSION: Mild to moderate alcohol consumption, especially red wine consumption, in obese subjects is associated with lower fasting homocysteine concentrations. This may reduce cardiovascular risk and help explain the 'French paradox'.

Adult↗

PubMed2001

Sleep disturbance and obesity: changes following surgically induced weight loss.

BACKGROUND: Obesity causes sleep disturbance and is the most significant risk factor for sleep apnea. Only surgical methods provide substantial sustained weight loss for most severely obese subjects. OBJECTIVE: To study sleep disturbance in patients undergoing laparoscopic adjustable gastric banding with a commercially available product (Lap-Band). METHODS: In this study, 313 consecutive patients with severe obesity (body mass index [calculated as weight in kilograms divided by the square of height in meters] >35) completed a preoperative sleep questionnaire and clinical assessment. One hundred twenty-three patients completed the same assessment 12 months after surgery. The characteristics of sleep disturbance and changes in responses to weight loss have been assessed. RESULTS: There was a high prevalence of significantly disturbed sleep in men (59%) and women (45%), with women less likely to have had their sleep disturbance investigated. Observed sleep apnea was more common in men, but daytime sleepiness was not affected by sex. Waist circumference was the best clinical measure predicting observed sleep apnea (R = 0.36; P<.001). The group lost an average of 48% (SD, 16%) of excess weight by 12 months. There was a significant improvement in the responses to all questions at follow-up, with habitual snoring reduced to 14% (preoperative value, 82%), observed sleep apnea to 2% (preoperative value, 33%), abnormal daytime sleepiness to 4% (preoperative value, 39%), and poor sleep quality to 2% (preoperative value, 39%) (P<.001 for all). CONCLUSIONS: Obesity-related sleep disorders improve markedly with weight loss. Sustainable weight loss should be a primary aim in the management of severely obese patients with significant sleep disturbance, including sleep apnea. Low-risk laparoscopic obesity surgery should be considered for selected patients with this important comorbidity.

Body Mass Index↗

PubMed2001

Inhibition of beta-catenin translocation in rodent colorectal tumors: a novel explanation for the protective effect of nonsteroidal antiinflammatory drugs in colorectal cancer.

In a rodent colorectal cancer model, nonsteroidal antiinflammatory drugs reduce tumor mass by increasing the rate of tumor cell apoptosis and decreasing proliferation. We have examined beta-catenin as a potential target for these agents in colorectal cancer. Carcinogen-treated rats were treated for 23 weeks with a range of nonsteroidal antiinflammatory drugs. Control animals received vehicle alone. Intracellular beta-catenin was examined using immunohistochemistry. In tumors from untreated animals, staining was seen in the cytoplasm and nucleus (median 24% of nuclei). The frequency of nuclear beta-catenin staining correlated directly with the volume of tumor and inversely with the rate of apoptosis. In tumors from treatment groups, the cytoplasmic staining for beta-catenin was unchanged; however, nuclear staining was absent except in the celecoxib group, where it was reduced to a median of 14%. Colorectal tumors from animals treated with NSAIDs show reduced levels of nuclear beta-catenin immunoreactivity.

1,2-Dimethylhydrazine↗

PubMed2001

Quality of life after lap-band placement: influence of time, weight loss, and comorbidities.

OBJECTIVE: To assess the quality of life (QOL) in severely obese subjects before and after Lap-Band gastric restrictive surgery and identify factors that may influence change. RESEARCH METHODS AND PROCEDURES: All patients, over a 3-year period, attending for preoperative assessment (n = 459) or annual review after surgery (n = 641) have completed the Short Form-36 (SF-36) health survey. Eight domain and physical component summary (PCS) and mental component summary (MCS) scores were calculated. Scores were analyzed in groups based on time after surgery and compared with community normal (CN) values. Paired preoperative and 1-year scores (n = 218) data were used to find predictors of QOL change. RESULTS: All preoperative mean scores (n = 459) were lower than CN values, with greater impairment in the PCS (36.8 +/- 9.5 vs. CN: 51.3 +/- 8.3, p < 0.001) than in the MCS (45.7 +/- 8.2 vs. CN: 48.8 +/- 9.5, p < 0.001) scores. After 1 year, scores were closer to CN scores (PCS: 52.4 +/- 8.2 and MCS: 48.4 +/- 7.7), and these remained closer for 4 years. Preoperative obesity comorbidity, especially physical disability, was the best predictor of poor preoperative SF-36 scores and of improvement in scores at 1 year. The percentage of excess weight loss at 1 year (46 +/- 16%) was of little predictive value of improved QOL. DISCUSSION: Severely obese subjects have poor health-related QOL as measured by the SF-36 health survey. Lap-Band surgery for this group has provided a dramatic and sustained improvement in all measures of the SF-36. Improvement is greater in those with greater preoperative disability, and the extent of weight loss is not a good predictor of improved QOL.

Adult↗

PubMed2001

Elevated homocysteine levels with weight loss after Lap-Band surgery: higher folate and vitamin B12 levels required to maintain homocysteine level.

OBJECTIVE: To investigate homocysteine levels and their relationship with serum folate and vitamin B12 concentrations with weight loss after the Lap-Band form of gastric restrictive surgery, with the view to minimizing risk. METHODS: We measured levels of fasting plasma homocysteine (tHcy), folate (serum and RBC) and vitamin B12 in two groups. The study group was 293 consecutive patients at 12 (n=192) or 24 (n=101) months review after surgery. The controls were 244 consecutive patients presenting for this surgery. RESULTS: The group losing weight had higher geometric mean tHcy levels: 10.4 (95% CI, 9.8-10.8) micromol/l compared with 9.2 (95% CI, 8.9-9.7) in controls (P<0.001). This occurred with higher folate levels and unchanged vitamin B12 levels. Levels of folate and B12 together explained 35% (r (2)) of the homocysteine variance in the weight loss group compared with only 9% (r (2)) in controls (P<0.001). Those taking regular multivitamin supplements had lower tHcy levels: 9.6 (9.1-10.0) micromol/l vs 12.3 (11.4-13.3) in those not taking supplements (P<0.001). A low normal plateau of tHcy levels occurred at levels of folate >15 ng/l and B12)600 ng/ml. A curvilinear relationship exists between these cofactors and tHcy levels, with the dose-response relationship shifted to the right in the weight loss group. CONCLUSION: This study shows elevated tHcy levels with weight loss, without lower serum folate or vitamin B(12) levels. There is an altered dose-response relationship with higher serum B(12) and folate levels required to maintain recommended tHcy levels. Patients losing weight have significant health benefits; however, they may be at greater risk of vascular events or fetal abnormality in association with raised tHcy levels. Multivitamin supplementation is effective in lowering tHcy levels.

Adult↗

PubMed2001

Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is common in severely obese subjects and can progress to cirrhosis and liver failure. Predicting advanced or progressive disease may help in selecting patients for liver biopsy and assist the development of therapeutic options. METHODS: Liver biopsies were taken at laparoscopic obesity surgery in 105 consecutive patients. The clinical and biochemical variables were analyzed for correlation with specific histologic features. RESULTS: Twenty-six patients (25%) were found to have nonalcoholic steatohepatitis (NASH), and 11 (42%) of these had advanced fibrosis. A raised index of insulin resistance (odds ratio [OR] 9.3, 95% confidence interval [CI] 3.4-26), systemic hypertension (OR 5.2, 95% CI 2.0-13.5), and raised alanine aminotransferase (OR 8.6, 95% CI 3.1-23.5) were independent predictors of NASH. A combination of 2 or 3 of these predictors allows a sensitivity of 0.8 and specificity of 0.89 for NASH. Alcohol consumption was associated with a reduction in NASH (OR 0.35, 95% CI 0.12-1.00) and diabetes (OR 0.18, 95% CI 0.047-0.67). CONCLUSION: Insulin resistance and systemic hypertension, features of the metabolic syndrome, are independently associated with advanced forms of NAFLD. Moderate alcohol consumption seems to reduce the risk of NAFLD in the severely obese, possibly by reducing insulin resistance.

Adult↗

PubMed2001

Rat colorectal tumours treated with a range of non-steroidal anti-inflammatory drugs show altered cyclooxygenase-2 and cyclooxygenase-1 splice variant mRNA expression levels.

Non-steroidal anti-inflammatory drugs (NSAIDs) reduce tumour mass by increasing the rate of tumour cell apoptosis and decreasing cell proliferation. The classically recognized target for NSAID action are the two isoforms of the cyclooxygenase (COX) gene, which is responsible for prostaglandin production. In the rat, the COX-1 gene expresses an alternatively spliced mRNA COX-1 splice variant (SV) which may, at best, code for a truncated COX-1 protein. Previously, we reported that COX-1SV mRNA is differentially expressed in the ageing stomach. In this study, carcinogen treated rats were treated for 23 weeks with celecoxib, sulindac or sulindac sulfone, while untreated rats received vehicle alone. For each animal, the number and volume of tumour per animal was recorded and histology was performed. Using competitive polymerase chain reaction, we determined whether COX gene expression was altered in colorectal tumours and in regions of adjacent and distant macroscopically normal intestine, from vehicle or NSAID treated rats. In addition, we immunolocalized COX-1 and COX-2 in the same tumour and normal colonic tissue. Tumours from animals treated with vehicle or celecoxib expressed significantly elevated levels of COX-2 mRNA in comparison with the adjacent normal mucosa. In contrast, tumours from sulindac and sulindac sulfone treated rats expressed significantly less COX-2 mRNA than tumours from vehicle treated rats. The expression of COX-1 mRNA remained unchanged in all tissues examined. However, COX-1SV mRNA levels were elevated in colorectal tumours and reduced after NSAID treatment to the levels observed in normal colonic mucosa. Our results indicate that the anti-neoplastic actions of NSAIDs may be attributed to COX dependent and/or COX independent mechanisms of action. We also demonstrate the presence and differential expression of COX-1SV mRNA in colon tumours. COX-1SV mRNA represents 2% of the total COX-1 mRNA expressed and its role in colon cancer remains to be established.

Adenocarcinoma↗

PubMed2001

Non-steroidal anti-inflammatory drugs with activity against either cyclooxygenase 1 or cyclooxygenase 2 inhibit colorectal cancer in a DMH rodent model by inducing apoptosis and inhibiting cell proliferation.

BACKGROUND: Standard non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colorectal cancer by 40-60% but the mechanism by which this occurs is uncertain. Selective cyclooxygenase 2 inhibitors are potentially ideal chemopreventive agents as they are less toxic than standard NSAIDs. No study has compared the efficacy of these drugs at clinically relevant doses in a tumour model. AIMS: To assess the efficacy of a range of NSAIDs with varying activity against the two cyclooxygenase isoforms in a rodent colorectal carcinogen model at anti-inflammatory doses and to explore the effect of NSAIDs on the rate of tumour apoptosis and proliferation. METHODS: Colorectal tumours were induced in six week old Sprague-Dawley rats with five weekly doses of 1,2 dimethylhydrazine. Test agents were: indomethacin 2 mg/kg/day, meloxicam 0.6 mg/kg/day, celecoxib 6 mg/kg/day, and sulindac sulphone 40 mg/kg/day. Sulindac was tested at its chemoprotective dose of 20 mg/kg/day. After 23 weeks the number and volume of tumours per animal were recorded. Histology was performed. Tumour apoptosis was quantified on haematoxylin-eosin sections. Tumour proliferation was quantified using an immunohistochemical stain for bromodexoyuridine incorporation. RESULTS: Test agents effectively reduced the number and volume of tumours developing in the treatment period. In all groups there was an increase in the rate of tumour apoptosis and a reduced rate of proliferation. CONCLUSIONS: These data suggest that the chemopreventive effect of NSAIDs is independent of their cyclooxygenase inhibitory profile. One potential mechanism for their action may be through induction of apoptosis and inhibition of proliferation.

Adenocarcinoma↗

PubMed2001

Pregnancy after Lap-Band surgery: management of the band to achieve healthy weight outcomes.

BACKGROUND: Severely obese women have higher obstetric risks and poorer neonatal outcomes. Weight loss reduces obstetric risk. The introduction of a laparoscopically-placed adjustable gastric band, a safe and effective method of weight loss, has given us the ability and responsibility to adjust the band in relation to pregnancy. OBJECTIVE: Our aim was to devise a safe management plan to achieve healthy maternal weight gain (Institute of Medicine 1990) during pregnancy. METHODS: In a cohort group of 650 patients to have a Lap-Band placement for severe obesity, we have reviewed the management of the band and pregnancy outcomes of all women (n=20) to complete a pregnancy (n=22) with a band in-situ. RESULTS: All 22 pregnancies were singleton, with no primary caesarean sections (3 for recurring indications). The mean maternal weight gain was 8.3 kg compared with 15.2 kg for the 15 previous pregnancies of women in this group (p<0.05). There was no difference in birth weights. Obstetric complications were minimal, and there were no premature or low birth weight infants. 11 of 15 subjects with active management of the band achieved a maternal weight gain within the advised range compared with only 2 of 7 prior to this. CONCLUSION: The ability to adjust gastric restriction allows optimal control of maternal weight change in pregnancy and should help avoid the risks of excessive weight change.

Adult↗

PubMed2001

Pre-operative predictors of weight loss at 1-year after Lap-Band surgery.

BACKGROUND: The authors studied a range of preoperative factors for their predictive value of effectiveness of Lap-Band placement, using the percentage of excess weight loss at 1-year as the outcome measure (%EWL1). METHODS: All factors were measured and recorded prior to surgery. Factors included: patient demographics, family, medical and weight history. Laboratory measures and the responses to the SF-36 Health Survey were also assessed. Factors were assessed for correlation with %EWL1. RESULTS: The group (N=440, F:M 383:57) had mean age 40.0+/-9.5 years, weight of 126+/-25 kg, and BMI 45.6+/-7.5 kg/m2 pre-operatively. At 1-year follow-up, the group had mean weight 97.6< or =20 kg, BMI 35.6 = 6.3 kg/m2, and %EWL1 45.8< or =17%. Increasing age (R= -0.13, p<0.01) and preoperative BMI (R=-0.22, p<0.001) were significantly associated with less %EWL1 and all other factors were controlled for these before assessing significance. Important factors associated with a lower %EWL1 included: hyperinsulinemia (R=-0.36, p<0.001), insulin resistance (R=-0.33, p<0.001) and disease associated with insulin resistance, poor physical ability, pain, and poor general health responses to the SF-36 Health Survey. Patients who consumed alcohol regularly had a better rate of weight loss (R= 0.23, p<0.005). Factors that had no influence included gender, a history of mental illness and measures of mental health, previous bariatric surgery, and a history of many medical conditions associated with obesity. CONCLUSION: Important physical factors have been found to influence the rate of weight loss. Those with increased age, pain, physical disability and insulin resistance have a great deal to gain from weight loss. Although this study has identified factors that are associated with less weight loss, we have not found any factor that predicts an unacceptably low weight loss and thus provides a contraindication to Lap-Band placement. The findings of this study allow us to set more realistic goals for the rate of weight loss in specified sub-groups of our patients.

Adult↗

PubMed2001

Combretastatin A4 prodrug study of effect on the growth and the microvasculature of colorectal liver metastases in a murine model.

Combretastatin A4P (CA4P) is a prodrug that, in active form, binds to tubulin microtubules of capillary endothelial cells. Studies to date indicate it has significant activity as a specific tumor vascular targeting agent. The goals were to assess the effects of CA4P on tumor growth and microvasculature of colorectal liver metastases in the mouse model, using stereological and histological methods to measure tumor growth, and vascular corrosion casting and laser doppler flowmetry to assess effect on the microvasculature. Continuous s.c. infusion of CA4P produced a major reduction in tumor growth. The percentage of the liver occupied by metastases decreased from 20.55 +/- 13.3% in controls to 7.46 +/- 5.99% in treated animals (P = 0.03). Ultrastructural study of tumor microvasculature after a single dose of CA4P revealed marked effects 1 h after treatment. There was loss of patent microvessels at the normal liver-tumor interface. Central microvascular density was reduced, with constriction and tapering of vessels. CA4P appeared to cause no damage to normal liver tissue or vasculature. Tumor blood flow decreased from 37.6 +/- 13.9% in controls to 24.4 +/- 6.1% in tumors >5 mm in diameter, 1 h after treatment with CA4P (P < 0.03). Quantitative histology of tissue at 6 and 24 h after CA4P treatment showed a significant increase in tumor necrosis (48.7 +/- 21% and 55.5 +/- 19% compared with controls, 20.6 +/- 8%; P = 0.01). Continuous infusion with CA4P causes marked reduction in tumor volume. A single dose of CA4P causes major changes of the tumor microvasculature, reduction of tumor blood flow, and increase in tumor necrosis. CA4P has a potential role in the management of patients with liver metastases.

Animals↗

PubMed2000

Restoring control: the Acticon Neosphincter artificial bowel sphincter in the treatment of anal incontinence.

PURPOSE: Anal incontinence is a socially disabling problem affecting 1 to 2 percent of the population. Anal sphincter replacement is a treatment option if the problem is severe and not amenable to direct repair. The artificial bowel sphincter is an innovative approach. We report the technique for placement and the outcomes which have occurred in an initial series of 13 patients. METHODS: The Acticon Neosphincter artificial bowel sphincter consists of an inflatable cuff of silicone elastomer placed around the anal canal and connected to a pressure-regulating balloon in the iliac fossa via a control pump placed in the labium or scrotum. Thirteen patients with severe anal incontinence not amenable to other methods were treated. Causes of incontinence included obstetric damage in eight patients, surgical damage in two patients, imperforate anus in two patients, and spina bifida in one patient. RESULTS: Surgical placement of the device was straightforward, mean operating time was 65 minutes, and median length of stay was 3.6 days. One infection of the perineal wound occurred in the early postoperative period necessitating removal of the device. In two further patients the artificial bowel sphincter was removed because of late infection in one at seven months and because of erosion through the skin in another at three months. The artificial bowel sphincter has been activated in ten patients resulting in full continence to solids and liquids except in one patient with postvagotomy diarrhea who had some leakage of liquids during episodes of diarrhea. The mean (+/- standard deviation) continence score (Cleveland Clinic system; maximal incontinence = 20) changed from 18.7 +/- 1.6 preoperatively to 2.1 +/- 2.6 after activation (P < 0.0001). Quality of life measured using a continence-specific series of up to 39 questions changed from 77 +/- 16 percent of maximal reduction of quality preoperatively to 12 +/- 19 percent postoperatively (P < 0.001). CONCLUSIONS: The artificial bowel sphincter can be placed without technical difficulty and with low morbidity. Preliminary experience shows full restoration of continence in most patients and ease of use. Longer follow-up is needed to determine the extent of problems with infection, erosion, and mechanical failure.

Adult↗

PubMed2000

5-aminosalicyclic acid and olsalazine inhibit tumor growth in a rodent model of colorectal cancer.

The ability of 5-aminosalicylic acid and olsalazine to inhibit colonic aberrant crypts and tumors was investigated in 1,2-dimethylhydrazine-treated rats. The effect of these drugs on the rates of tumor apoptosis and proliferation was studied as potential mechanisms for their action. 5-Aminosalicylic acid reduced the number of aberrant crypt foci by over one third, while olsalazine had no effect on this parameter. However, both agents effectively reduced tumor number and load, increased the rate of tumor apoptosis, and reduced the rate of tumor cell proliferation. In conclusion, 5-aminosalicylic acid and olsalazine are both ultimately effective chemopreventive agents in this model; however, only 5-aminosalicylic acid inhibited the formation of aberrant crypt foci. The inhibitory effect of these agents in tumors is related to the inhibition of proliferation and the induction of apoptosis.

Aminosalicylic Acids↗

PubMed2000

Non-steroidal anti-inflammatory drugs with different cyclooxygenase inhibitory profiles that prevent aberrant crypt foci formation but vary in acute gastrotoxicity in a rat model.

BACKGROUND: Standard non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colorectal cancer; however, their use as preventive agents is limited by their inherent toxicity. Drugs that selectively inhibit cyclooxygenase-2 (COX-2) may be useful in this setting as they are supposedly less toxic. No study has directly compared the ability of standard NSAIDs and selective COX-2 inhibitors to inhibit colorectal cancer at clinically relevant doses. METHODS: Aberrant crypt foci (ACF) were induced in Sprague-Dawley rats by using 1,2-dimethylhydrazine (DMH). Test agents or vehicle were then administered for 3 weeks, twice daily through orogastric gavage. At the end of this period, the number and multiplicity of ACF were determined. The agents tested at equivalent anti-inflammatory doses were: sulindac and indomethacin (standard NSAIDs), meloxicam (selective COX-2 inhibitor), celecoxib (specific COX-2 inhibitor) and sulindac sulfone (no known COX activity). Acute gastrotoxicity of NSAID in rats was compared by using quantitative histology. RESULTS: All test agents reduced the number of ACF. There was a 42% reduction with indomethacin, 46% with sulindac, 46% with meloxicam, 22% with celecoxib and 36% with sulindac sulfone. Only the COX-2 inhibitors caused no significant gastrotoxicity in rats. CONCLUSIONS: Cyclooxygenase-2 inhibitors are potentially ideal chemopreventive agents as they inhibit ACF and are not gastrotoxic.

Acute Disease↗