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Biomedical subjects

R S McLeod

Publications and source records attributed to R S McLeod.

At least 19 recordsLinked to original sources
PubMed1997

Normal activity of microsomal triglyceride transfer protein is required for the oleate-induced secretion of very low density lipoproteins containing apolipoprotein B from McA-RH7777 cells.

The requirement of the activity of microsomal triglyceride transfer protein (MTP) for very low density lipoprotein (VLDL) secretion was determined using McA-RH7777 cells stably transfected with human apoB48 (hB48). Secretion of VLDL containing hB48 (hB48-VLDL) by the transfected cells was induced by exogenous oleate (0.4 mM), and oleate-dependent VLDL secretion was selectively inhibited by brefeldin A (0.2 microg/ml). Two protocols were used to determine the effect of MTP inhibition on VLDL secretion. In the first protocol, cell protein and lipid were labeled with radioactive amino acids and oleate prior to MTP inhibition (using 5 microM of the photoaffinity inhibitor BMS-192951 to reduce MTP activity by 65-70%), and secretion of prelabeled apoB and triacylglycerol (TG) associated with lipoproteins was monitored during oleate-supplemented chase. In control cells, a 6-fold increase in incorporation of prelabeled TG into hB48-VLDL was observed after oleate supplement, while incorporation of prelabeled TG into VLDL containing endogenous rat apoB100 (rB100-VLDL) was unaffected. Inhibition of MTP activity abolished the oleate-induced utilization of prelabeled TG (by 80%) and hB48 (by 70%) for hB48-VLDL secretion but decreased utilization of pre-existing TG (by <25%) and B100 (by 45%) for rB100-VLDL secretion to a lesser extent. Inhibition of MTP did not affect incorporation of prelabeled TG or hB48 into high density lipoproteins containing hB48 (hB48-HDL). In the second protocol, MTP was inactivated prior to metabolic labeling of protein and lipid, and secretion of newly labeled apoB and TG as lipoproteins was monitored after oleate supplement. Under this condition, MTP inhibition decreased incorporation of newly labeled TG (by 80%) and hB48 (80%) into hB48-VLDL but did not affect their incorporation into hB48-HDL. Additionally, MTP inhibition decreased incorporation of newly labeled TG (by 50%) and rB100 (by 90%) into rB100-VLDL. Thus, normal activity of MTP is required for the oleate-induced secretion of hB48-VLDL from McA-RH7777 cells.

Animals↗
PubMed1997

Risk factors for pelvic pouch failure.

PURPOSE: This study was designed to identify factors associated with pelvic pouch failure. METHOD: A retrospective review of patients undergoing the pelvic pouch procedure with a minimum of 30 months follow-up was conducted. RESULTS: A total of 551 patients had pelvic pouch procedures from 1981 to 1992. Forty-nine patients (8.8 percent) have undergone pouch excision, and 9 (1.6 percent) have been defunctioned, for 58 (10.5 percent) patients with pouch failure. Cause of failure was leakage from the ileoanal anastomosis (IAA) in 21 (39 percent) patients, poor functional results in 13 (23 percent), pouchitis in 7 (12 percent), pouch leakage in 7 (12 percent), perianal disease in 7 (12 percent), and miscellaneous in 3 (5.2 percent). Nine of 22 patients (41 percent) had pouch failure during the first two years, with 2 of 147 patients (1 percent) having failure during the last two years of the study. The 58 patients whose pouches failed (Group 1) were compared with the 493 patients whose pouches did not fail (Group 2). Handsewn IAA (P < 0.001), tension on the IAA (P < 0.001), use of a defunctioning ileostomy (P < 0.01), a diagnosis of Crohn's disease (P < 0.001), and a leak from the pouch (P < 0.001) or the IAA (P < 0.001) were associated with pouch failure. Pouchitis was not a risk factor. CONCLUSION: The majority of pouch failures were caused by leaks at the IAA. Although the leak rate remained stable, leaks following a stapled anastomosis seemed to have a better prognosis than leaks following a handsewn anastomosis. Experience with the pouch procedure and the management of complications likely plays an important role in decreasing the risk of pouch failure.

Adult↗
PubMed1997

Preliminary report on the Mount Sinai Hospital Inflammatory Bowel Disease Genetics Project.

BACKGROUND: Although the etiology of inflammatory bowel disease (IBD) is unknown, there is increasing evidence that genetic predisposition plays a major etiologic role. To provide the framework for gene identification using a positional cloning approach, ascertainment of families with multiple affected members and careful documentation of pedigrees are essential. OBJECTIVE: To report the initial findings of the IBD Genetics Project of the Mount Sinai Hospital IBD Research Unit. METHODS: All records of patients with ulcerative colitis and Crohn's disease followed at the Mount Sinai Hospital IBD Unit were reviewed. A questionnaire was sent to all patients to ascertain those with a family history of IBD. Patients with a presumed family history were contacted by a research assistant, and after confirmation of diagnosis, relevant clinical information, pedigrees, and consent to contact family members were obtained. Blood for DNA and cell line preparation were collected from affected and nonaffected family members. RESULTS: Of 2,504 patients registered in the IBD database, 231 (9.2 percent) were found to have an affected family member: 96 of 964 (10 percent) with Crohn's disease (CD) and 135 of 1,540 (8.8 percent) with ulcerative colitis (UC). A mean of 2.4 family members were affected. In families in which the proband had CD, 82.3 percent had only two affected family members, 78.1 percent had only family members affected with CD, and 82.3 percent had only first-degree family members affected. In families in which the proband had UC, 70.4 percent had only two affected family members, 71.1 percent had only family members affected with UC, and 65.2 percent had only first-degree family members affected. In the 231 families, there were 103 sibling pairs: 46 percent with CD, 28 percent with UC, and 26 percent with CD/UC. CONCLUSION: These data suggest that approximately 10 percent of IBD patients have affected family members, with the rate being similar in UC and CD. Future research is directed to genome scanning and linkage analysis in this cohort of patients.

Colitis, Ulcerative↗
PubMed1997

Outcome of the pelvic pouch procedure in patients with prior perianal disease.

PURPOSE: There is concern that patients with presumed ulcerative colitis and significant perianal disease may in fact have Crohn's disease. Moreover, prior perianal disease may be an independent factor for poor outcome of the pelvic pouch. The aim of this study was to evaluate the effect of prior perianal disease on pelvic pouch outcome. METHODS: Between 1982 and 1994, 52 of 753 patients (6.9 percent) who had a pelvic pouch procedure were prospectively identified as having perianal disease. Outcome of the pelvic pouch of these 52 patients (Group I) were compared with the outcome of 701 pelvic pouch patients with no prior perianal disease (Group II). The perianal diseases identified in Group I were fissure-in-ano (17), perianal abscesses (13), fistula-in-ano (7), rectovaginal fistula (3), and significant hemorrhoids/skin tags (25). Eleven patients (21 percent) had more than one type of perianal disease. Twenty-seven patients (52 percent) required a total of 33 perianal operations for the different anal pathologies. RESULTS: Both groups were comparable for the following characteristics: age at time of pelvic pouch procedure, pathology (ulcerative colitis or indeterminate colitis), design of pouch, and type of ileoanal anastomosis (handsewn or stapled). An ileoanal anastomosis leak developed in 21 percent of patients (n = 11) in Group I vs. 11.4 percent (n = 80) in Group II (P < 0.05). Perianal postoperative complications occurred in 11.5 percent of patients (n = 6) in Group I vs. 1.7 percent (n = 12) in Group II (P < 0.05). Total pouch failure rate was not significantly different between the two groups (11.5 vs. 7.6 percent; P > 0.05). Crohn's disease was subsequently diagnosed in 1.9 vs. 2.7 percent (P > 0.05). Subgroup analysis of Group I patients showed no significant difference in outcome according to type of perianal lesion or a history of perianal surgery. CONCLUSION: Prior perianal disease significantly increases the risk of developing an ileoanal anastomotic leak and postoperative perianal complications. However, a pelvic pouch procedure may be an acceptable surgical alternative for selected ulcerative colitis patients with prior perianal disease because the overall pouch failure rate is not significantly increased.

Adult↗
PubMed1997

Comparison of hemorrhoidal treatments: a meta-analysis.

OBJECTIVE: To determine whether any method of hemorrhoid therapy has been shown to be superior in randomized trials. METHOD: A meta-analysis of all randomized controlled trials assessing two or more treatment modalities for symptomatic hemorrhoids. MAIN OUTCOME MEASURES: Response to therapy, the need for further therapy, complications and pain. RESULTS: Eighteen trials were available for analysis. Hemorrhoidectomy was found to be significantly more effective than manual dilatation of the anus (p = 0.0017) and associated with less need for further therapy (p = 0.034), no significant difference in complications (p = 0.60) but more pain (p < 0.001). Patients who underwent hemorrhoidectomy had a better response to treatment than did patients who were treated with rubber-band ligation (p = 0.001), although complications were greater (p = 0.02), as was pain (p < 0.0001). Rubber-band ligation was better than sclerotherapy in response to treatment for all hemorrhoids (p = 0.005) and for hemorrhoids stratified by grade (grades 1 and 2, p = 0.007, grade 3, p = 0.042), with no difference in the complication rate (p = 0.35). Patients treated with sclerotherapy (p = 0.031) or infrared coagulation (p = 0.0014) were more likely to require further therapy than those treated with rubber-band ligation, although pain was greater after rubber-band ligation (p = 0.03 for sclerotherapy, p < 0.0001 for infrared coagulation). CONCLUSIONS: Rubber-band ligation is recommended as the initial mode of therapy for grades 1 to 3 hemorrhoids. Although hemorrhoidectomy showed better response, it is associated with more complications and pain than rubber-band ligation. Thus, it should be reserved for patients whose hemorrhoids fail to respond to rubber-band ligation.

Diathermy↗
PubMed1996

Apolipoprotein B sequence requirements for hepatic very low density lipoprotein assembly. Evidence that hydrophobic sequences within apolipoprotein B48 mediate lipid recruitment.

We studied the structural requirements of apolipoprotein (apo) B for assembly of very low density lipoproteins (VLDL) using rat hepatoma McA-RH7777 cells expressing human apoB (h-apoB). Recombinant h-apoB48, like endogenous rat apoB48 (r-apoB48), was secreted as VLDL in addition to high density lipoproteins (HDL) by transfected cells, indicating that the N-terminal 48% of apoB contains sequences sufficient for VLDL assembly. Truncation of the C terminus of h-apo-B48 to -B42 or -B37 had little effect on the ability of apoB to assemble VLDL, whereas truncation to -B34 or -B29 markedly diminished or abolished VLDL formation. None of the truncations affected the integration of apoB into HDL. To determine whether the ability to assemble VLDL is governed by apoB length or by sequences beyond apoB29, we created chimeric proteins that contained human apoA-I and a segment derived from between the C-terminal 29 and 34%, 34 and 37%, or 37 and 42% of apoB100. The resulting chimeras, namely AI/B29-34, AI/B34-37, and AI/B37-42, were secreted by the transfected cells as lipoproteins with buoyant density (d < 1.006 g/ml), electrophoretic mobility (pre-beta), and size characteristics of human plasma VLDL. The chimeras could assemble discrete VLDL particles devoid of endogenous r-apoB100, and could actively recruit triglycerides and phospholipids into the lipoproteins. However, these chimeras were secreted inefficiently. Pulse-chase analysis showed that less than 5% of the newly synthesized AI/B proteins were secreted, and more than 70% was degraded intracellularly. Degradation of the chimeras could be blocked by the cysteine protease inhibitor N-acetyl-leucyl-leucyl-norleucinal, but the treatment did not enhance their secretion. Protease protection analysis of microsomes isolated from transfected cells indicated that >65% of AI/B chimeras (compared with <25% of r-apoB100) were inaccessible to exogenous trypsin. These data suggest that the recruitment of large quantities of triglycerides during VLDL formation is not governed simply by apoB length, but is mediated by short hydrophobic sequences ranging from 152 to 237 amino acids (3-5%) of apoB. The existence of multiple such hydrophobic sequences within apoB48 may facilitate efficient assembly of hepatic VLDL particles.

Animals↗
PubMed1996

The microsomal triglyceride transfer protein facilitates assembly and secretion of apolipoprotein B-containing lipoproteins and decreases cotranslational degradation of apolipoprotein B in transfected COS-7 cells.

We studied the role of microsomal triglyceride transfer protein (MTP) in the synthesis, secretion, and cotranslational degradation of apolipoprotein (apo) B using nonhepatic COS-7 cells that expressed C-terminally truncated forms of apoB (from apoB15 to apoB94) with or without the large subunit of human MTP. With the exception of apoB15 and apoB18, secretion of all of the apoB forms was stimulated by expression of MTP, even though a small amount of short apoB forms (</=apoB48) could be secreted by cells transfected with apoB alone. The majority of the apoB protein, including apoB72 and apoB94, was secreted as high density lipoprotein (1.08-1.17 g/ml). Pulse-chase experiments revealed that the secretion efficiency of apoB94 and apoB72 was low (ranging from 2 to 12%). The failure to secrete buoyant lipoproteins and the low secretion efficiency were associated with insufficient lipid synthesis by the cells. The incorporation of [3H]oleate into cellular triglyceride and phosphatidylcholine by COS cells over a 2-h period was 28 and 38%, respectively, of that by rat hepatoma (McA-RH7777) cells. In addition to the desired full-length apoB, cells transfected with large constructs (>/=apoB60) also produced smaller species with a size of approximately220 kDa (designated B48-like protein). Coexpression with MTP decreased formation of the B48-like proteins by 40-60%. The reduction in B48-like protein formation was specific to MTP expression; coexpression with other proteins (e.g. apoA-I or apoB15) did not alter B48-like protein production. Kinetic analysis suggested that B48-like proteins were produced concurrently (cotranslational) with the full-length apoB94 and apoB72 and were not products of post-translational degradation. Although some of the B48-like proteins might be derived from truncated species (approximately 7 kb in size) of apoB mRNA that were found in cells transfected with large apoB constructs, MTP coexpression did not affect the relative levels of the aberrant 7-kb RNA with respect to the full-length mRNA. However, coexpression of MTP decreased the accessibility of apoB to exogenous trypsin by 2-fold for apoB72 and by 10-fold for apoB94 in isolated microsomes. Thus, the reduced B48-like protein formation by MTP may be a consequence of attenuated cotranslational degradation during apoB translocation across the ER membrane. Formation of B48-like proteins was insensitive to N-acetyl-leucyl-leucyl-norleucinal, a cysteine protease inhibitor known to block post-translational degradation of apoB. These results indicate that MTP facilitates the assembly and secretion of lipoproteins containing apoB and also attenuates the formation of B48-like proteins, probably by assisting apoB translocation across the ER membrane.

Animals↗
PubMed1996

Ileal pouch-anal anastomosis: pregnancy, delivery and pouch function.

OBJECTIVE: To evaluate the pregnancies, deliveries and functional results of patients who have undergone and ileal pouch-anal anastomosis. DESIGN: A retrospective survey by questionnaire. SETTING: The study was conducted at a university hospital. SUBJECTS: Twelve women who had undergone an ileal pouch-anal anastomosis at the Inflammatory Bowel Disease Centre, Mount Sinai Hospital and who had subsequently become pregnant, were identified from the hospital records. A follow up questionnaire was completed by all subjects. RESULTS: Twelve patients had 16 deliveries. There were 10 vaginal deliveries and 6 caesarian sections. There were no pouch-related complication during the 16 pregnancies and there were two postpartum complications. CONCLUSIONS: Pregnancy is safe in women with an ileal pouch-anal anastomosis. Functional results are altered minimally. Vaginal delivery is safe and obstetric reasons should determine whether a caesarian section is performed.

Adolescent↗
PubMed1996

Nutritional status and function in patients following Whipple procedure compared with controls.

OBJECTIVE: Despite the potential for nutritional deficits in patients undergoing pancreaticoduodenectomy or Whipple procedure, long-term assessment of nutritional status has largely been ignored. This study assessed nutritional status of 24 Whipple patients compared with matched post-cholecystectomy controls. METHODS: Clinical assessment was by subjective global assessment, body composition was assessed by bioelectric impedance analysis and functional assessment was by respiratory muscle strength and skeletal muscle function performed by electrical stimulation of the ulnar nerve of the wrist and hand-grip dynamometry. RESULTS: Whipple patients studied 4.6+/-0.7 years since surgery and controls (4.8+/-0.7 years since surgery) were all judged clinically to be in a good nutritional state. Compared with controls, Whipple patients had significantly lower body weight (Whipple: 72.5+/-2.8 kg, control: 83.9+/-3.3 kg, p<0.05) however, the mean body weight of both Whipple and controls was above ideal weight (Whipple: 113.3+/-4.3%, control: 122.3+/-3.7% p = NS). No significant differences in functional performance were observed between groups. Energy intake of Whipple and controls was also comparable. In the Whipple group, neither the extent of gastric resection or the pathological diagnosis had an effect on the nutritional parameters studied. CONCLUSIONS: Long-term follow-up of patients having undergone Whipple procedure failed to reveal the presence of any nutritional or functional deficits suggesting that a full nutritional recovery is possible after this surgery.

Aged↗
PubMed1996

The risk of thromboembolism in patients undergoing colorectal surgery.

Patients undergoing colorectal surgical procedures are at a moderately high risk for the development of thromboembolic events. Possible reasons may be that the procedures tend to be long in duration, patients are often placed in the lithotomy position, a pelvic dissection may be performed, and the indication is often inflammatory bowel disease or cancer. While prophylaxis with low dose heparin is effective at reducing this risk, approximately 10% of patients may still develop a thromboembolic event. Results on the effectiveness of low molecular weight heparin in this cohort of patients are pending.

Anticoagulants↗
PubMed1996

Chemotherapy for desmoid tumours in association with familial adenomatous polyposis: a report of three cases.

OBJECTIVE: To determine the efficacy of chemotherapy for inoperable desmoid tumours associated with familial adenomatous polyposis. DESIGN: A review of three cases of unresectable desmoid tumours and of the literature on the subject. SETTING: The Steven Atanas Stavro Polyposis Registry at Mount Sinai Hospital in Toronto. PATIENTS: Three patients with symptomatic, unresectable desmoid tumours associated with familial adenomatous polyposis and unresponsive to conventional hormone therapy. INTERVENTION: A chemotherapy regimen of seven cycles of doxorubicin (dose ranging from 60 to 90 mg/m2) and dacarbazine (1000 mg/m2), followed by carboplatin (400 mg/m2) and dacarbazine. OUTCOME MEASURES: Clinical improvement and tumour regression demonstrated by computed tomography. RESULTS: In each of the three cases significant tumour regression was seen clinically and radiologically. CONCLUSIONS: Cytotoxic chemotherapy is an effective treatment for desmoid tumours associated with familial adenomatous polyposis. The chemotherapy should be started early in cases of symptomatic desmoid tumour unresponsive to conventional medical therapy.

Adenomatous Polyposis Coli↗
PubMed1995

Comparison of hemorrhoidal treatment modalities. A meta-analysis.

PURPOSE: The purpose of this study was to assess whether any method of hemorrhoid therapy has been shown to be superior in randomized, controlled trials. METHOD: A meta-analysis was performed of all randomized, controlled trials assessing two or more treatment modalities for symptomatic hemorrhoids. Outcome variables included response to therapy, need for further therapy, complications, and pain. RESULTS: A total of 18 trials were available for analysis. Hemorrhoidectomy was found to be significantly more effective than manual dilation of the anus (P = 0.0017), with less need for further therapy (P = 0.034), no significant difference in complications (P = 0.60), but significantly more pain (P < 0.0001). Patients undergoing hemorrhoidectomy had a better response to treatment than did patients treated with rubber band ligation (P = 0.001), although complications were greater (P = 0.02) as was pain (P < 0.0001). Rubber band ligation was better than sclerotherapy in response to treatment for all hemorrhoids (P = 0.005) as well as for hemorrhoids stratified by grade (Grades 1 to 2; P = 0.007; Grade 3 hemorrhoids, P = 0.042), with no difference in the complication rate (P = 0.35). Patients treated with sclerotherapy (P = 0.031) or infrared coagulation (P = 0.0014) were more likely to require further therapy than those treated with rubber band ligation, although pain was greater after rubber band ligation (P = 0.03 for sclerotherapy; P < 0.0001 for infrared coagulation). CONCLUSION: Rubber band ligation is recommended as the initial mode of therapy for Grades 1 to 3 hemorrhoids. Although hemorrhoidectomy showed better response rates, it is associated with more complications and pain than rubber band ligation, thus should be reserved for patients who fail to respond to rubber band ligation.

Hemorrhoids↗