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Biomedical subjects

S H Leveson

Publications and source records attributed to S H Leveson.

At least 19 recordsLinked to original sources
PubMed2005

Rifaximin-ciprofloxacin combination therapy is effective in chronic active refractory pouchitis.

OBJECTIVE: Treatment of chronic refractory pouchitis is often difficult and disappointing and some of the affected pouches subsequently fail. This study was conducted to evaluate the efficacy and tolerability of treatment with rifaximin, a nonabsorbable oral antibiotic with immunomdulatory functions, in combination with ciprofloxacin for chronic active refractory pouchitis. PATIENTS AND METHODS: Eight patients with chronic active refractory pouchitis were treated orally with a combination of rifaximin 1 g b.d and ciprofloxacin 500 mg b.d. for two weeks. Clinical assessment, endoscopic and histological evaluations were performed before and after therapy using the Pouchitis Disease Activity Index (PDAI) score. Improvement was defined as a decrease of at least three points in the PDAI score and remission as a PDAI score of 0. The Wilcoxon signed rank test was used to compare pre- and post-treatment PDAI scores. The long-term outcome of the treated patients was prospectively monitored. RESULTS: Seven of the eight patients either went into remission (n = 5) or improved (n = 2). The median (range) PDAI scores before and after therapy were 12 (9-18) and 0 (0-15), respectively, (P = 0.018). All patients were compliant and no side effects were reported. Pouchitis recurred in two of the seven responding patients but returned into remission after further courses of the same combination. After a median follow-up of 30 months, the seven responding patients still had satisfactory pouch function. CONCLUSION: Rifaximin-ciprofloxacin combination therapy is safe and objectively effective in chronic active refractory pouchitis and may salvage a significant percentage of 'at risk pouches'.

Adult↗
PubMed2004

The formation of AFB(1)-macromolecular adducts in rats and humans at dietary levels of exposure.

The levels of aflatoxin B(1)-DNA and aflatoxin B(1)-albumin adducts were investigated by accelerator mass spectrometry (AMS) in humans and rats following exposure to a known, dietary relevant amount of carbon-14 labeled aflatoxin B(1) ([(14)C]AFB(1)). The aims of the study were to: (a) investigate the dose-dependent formation of DNA and protein adducts at very low doses of AFB(1) (0.16 ng/kg-12.3 microg/kg) in the rat; (b) measure the levels of AFB(1)-albumin and AFB(1)-DNA adducts at known, relevant exposures in humans (c) study rat to human extrapolations of AFB(1)-albumin and DNA adduct levels. The results in the rat showed that both AFB(1)-albumin adduct and AFB(1)-DNA adduct formation were linear over this wide dose range. The order of adduct formation within the tissues studied was liver>kidney>colon>lung=spleen. Consenting volunteers received 1 microg ( approximately 15 ng/kg) of [(14)C]AFB(1) in a capsule approximately approximately 3.5-7 h prior to undergoing colon surgery. The mean level of human AFB(1)-albumin adducts was 38.8+/-19.55 pg [(14)C]AFB(1)/mg albumin/microg AFB(1)/kg body weight (b.w.), which was not statistically different to the equivalent dose in the rat (15 ng/kg) 42.29+/-7.13 pg [(14)C]AFB(1)/mg albumin/microg AFB(1)/kg b.w. There was evidence to suggest the formation of AFB(1)-DNA adducts in the human colon at very low doses. Comparison of the linear regressions of hepatic AFB(1)-DNA adduct and AFB(1)-albumin adduct levels in rat found them to be statistically similar suggesting that the level of AFB(1)-albumin adducts are useful biomarkers for AFB(1) dosimetry and may reflect the DNA adduct levels in the target tissue. [(14)C]AFB(1)-DNA and [(14)C]AFB(1)-albumin adducts were hydrolysed and analysed by HPLC to confirm that the [(14)C] measured by AMS was derived from the expected [(14)C]AFB(1) adducts.

Aflatoxin B1↗
PubMed2000

Spontaneous dissection of the abdominal aorta.

Acute dissection of the aorta is a vascular surgical emergency. The majority of dissections originate in the thoracic aorta. Dissection originating in the infrarenal abdominal aorta is very rare and, given the vagueness of presenting symptoms of uncomplicated dissection, diagnosis is very difficult in the early stages. In the absence of a pulsatile abdominal mass, acute uncomplicated aortic dissection should be considered in the differential diagnosis of sudden onset of abdominal and back pain. We report a case of spontaneous infrarenal abdominal aortic dissection occurring in an ostensibly normal aorta, and discuss the diagnostic dilemma and subsequent management of the patient.

Abdominal Pain↗
PubMed1999

Comparative biotransformation studies of MeIQx and PhIP in animal models and humans.

MeIQx and PhIP are putative carcinogenic heterocyclic amines formed during the cooking of meat and fish. Using accelerator mass spectrometry, we have investigated the metabolism and macromolecule binding of 14C-labelled MeIQx and PhIP in human cancer patients compared to the rat. Following oral administration of MeIQx and PhIP, more DNA adducts were formed in human colon tissue compared with rats. Differences were also observed between rats and humans in the metabolite profile and urine excretion for these compounds. These results suggest humans metabolise heterocyclic amines differently to laboratory rodents and question their use as models of human risk.

Animals↗
PubMed1999

Comparison of DNA-adduct and tissue-available dose levels of MeIQx in human and rodent colon following administration of a very low dose.

[2-14C]2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was administered orally (304 ng/kg body-weight dose based upon an average 70-kg-body-weight subject) to 5 human colon-cancer patients (58 to 84 years old), as well as to F344 rats and B6C3F1 mice. Colon tissue was collected from the human subjects at surgery and from the rodents 3.5 to 6 hr after administration. Colon DNA-adduct levels and tissue available doses were measured by accelerator mass spectrometry (AMS). The mean levels of MeIQx in the histologically normal colon tissue were not different among the human (97 +/- 26 pg MeIQx/g), rat (133 +/- 15 pg/g) or mouse (78 +/- 10 pg/g) tissues; and no difference existed between the levels detected in human normal and tumor tissue (101 +/- 15 pg/g). Mean DNA-adduct levels in normal human colon (26 +/- 4 adducts/10(12) nucleotides) were significantly greater (p < 0.01) than in rats (17.1 +/- 1 adduct/10(12) nucleotides) or mice (20.6 +/- 0.9 adduct/10(12) nucleotides). No difference existed in adduct levels between normal and tumor tissue in humans. These results show that MeIQx forms DNA adducts in human colon at low dose, and that the human colon may be more sensitive to the effects of MeIQx than that of mice or rats.

Administration, Oral↗
PubMed1998

Metabolism of the food-borne mutagen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline in humans.

The metabolism of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was investigated in five human volunteers given a dietary equivalent of 14C-labeled MeIQx. The amount of the dose excreted in urine ranged from 20.2% to 58.6%, with unmetabolized MeIQx accounting for 0.7-2.8% of the dose. Five principal metabolites were detected in urine, and four of the derivatives were characterized by on-line UV spectroscopy and by HPLC-MS following immunoaffinity chromatography. Two metabolites were identified as the phase II conjugates N2-(3,8-dimethylimidazo[4,5-f]quinoxalin-2-yl)sulfamic acid (MeIQx-N2-SO3(-)) and N2-(beta-1-glucosiduronyl)-2-amino-3,8-dimethylimidazo[4,5-f ]quinoxaline (MeIQx-N2-Gl). Two other metabolites were the cytochrome P450-mediated (P450) oxidation products 2-amino-8-(hydroxymethyl)-3-methylimidazo[4,5-f]quinoxaline (8-CH2OH-MeIQx), and N2-(beta-1-glucosiduronyl)-N-hydroxy-2-amino-3,8-dimethylimidaz o[4,5-f]quinoxaline (NOH-MeIQx-N2-Gl). The latter product is a conjugate of the genotoxic metabolite 2-(hydroxyamino)-3,8-dimethylimidazo-[4,5-f]quinoxaline (NHOH-MeIQx). A large interindividual variation was observed in the metabolism and disposition of MeIQx; these four metabolites and unchanged MeIQx combined accounted for 6.3-26.7% of the total dose. The remaining principal metabolite found in all subjects accounted for 7.6-28% of the dose. It has not been previously identified in rodents or nonhuman primates, and its structure remains unknown. P450-mediated ring oxidation of MeIQx at the C-5 position, a major pathway of detoxication in rodents, was not detected in humans. Both 8-CH2OH-MeIQx formation and NHOH-MeIQx formation are catalyzed by P450 1A2 and may be useful biomarkers of P450 1A2 activity in humans. The levels of NHOH-MeIQx-N2-Gl found in human urine ranged from 1.4% to 10.0% of the dose, which is significantly higher than that formed in rodents and nonhuman primates undergoing cancer bioassays. Thus, bioactivation of MeIQx by P450-mediated N-oxidation is extensive in humans.

Administration, Oral↗
PubMed1995

Low frequency and late occurrence of p53 and dcc aberrations in colorectal tumours.

Whilst p53 aberrations have been documented in numerous malignancies, reports of alterations to the deleted in colorectal cancer (dcc) gene are infrequent, and studies investigating the status of both genes in the same colon tumour are rare. In this study we have analysed a panel of 35 pairs of normal and neoplastic human colorectal tissues for abnormalities in these tumour-suppressor genes. In contrast to previous studies we have found only a low incidence of mutations and deletions. p53 point mutations were identified in 8/35 tumours (22%). All were G.C to A.T transitions, with 7/8 occurring at CpG dinucleotides. p53 allelic loss was detected in 4/11 informative cases (36%). Although not quite attaining statistical significance, p53 alteration correlated with the adenoma/carcinoma transition. Gross dcc alterations were identified by Southern blotting in 7/35 (20%) tumours. Microsatellite analysis using two markers, one within and one proximal to the dcc gene, detected a low frequency of deletion overall (41% informative cases). 18q/dcc aberrations were associated with the progression of early to late carcinoma, rather than with increasing adenoma size, as has been previously reported. Both p53 alterations and dcc deletions were detected at a higher frequency in distal tumours than in proximal malignancies. Two tumours exhibiting microsatellite instability in both markers were each of proximal origin.

Adult↗
PubMed1995

Limited role for intraoperative intact PTH measurement in parathyroid surgery.

Primary hyperparathyroidism may be cured surgically by complete excision of abnormal parathyroid tissue. Reoperation for persistent hypercalcaemia due to residual abnormal parathyroid tissue may be associated with a high complication rate. It is possible to assay intact parathormone (iPTH) intraoperatively and as iPTH has a relatively short half-life, its measurement intraoperatively may be used to predict successful parathyroidectomy. We have studied intraoperative iPTH levels in a consecutive series of 33 patients undergoing surgery for primary hyperparathyroidism. We found that iPTH levels fell significantly (P < 0.05) from a median pre-excision level of 122 pg/ml to a median level of 36 pg/ml 20 min after excision. However, in 3/31 successful parathyroidectomies, the intraoperative iPTH levels either remained unchanged or had risen. Reliance on intraoperative iPTH levels in these patients may have resulted in unnecessary re-exploration. We conclude that intraoperative iPTH measurement has limited usefulness as a predictor of successful parathyroidectomy for primary hyperparathyroidism.

Biomarkers↗
PubMed1989

Distal femoropopliteal bypass using a composite graft of PTFE and non-reversed saphenous vein.

The results of femoropopliteal bypass to the infragenicular popliteal artery, in the absence of suitable saphenous vein have, in the main, been disappointing. We present a new type of composite graft, for use when the distal anastomosis is below the knee, which avoids the potential problems of prosthetic graft alone. The graft consists of a proximal segment of 6 mm expanded PTFE (Gore-Tex; or Impra), anastomosed to transposed non-reversed autologous saphenous vein. Forty-two patients were studied following unilateral, below knee composite femoropopliteal graft surgery for severe claudication or critical ischaemia. Pressure indices were calculated along with intraoperative flow rate, and all patients were followed up at regular intervals to assess graft patency. During the study period three patients died and graft occlusion occurred in a further eight. Analysis of the cumulative patency curve revealed that the majority of occlusions occurred in the first 3 months. The patency at 12 and 18 months was encouraging with values of 84% and 79% respectively. Comparison of pressure indices revealed a significant increase following surgery (P less than 0.001). The postoperative pressure index appeared to predict the grafts likely to occlude and the intraoperative flow rates mirrored a similar trend. Grafts which occluded had a significantly lower pressure index and flow rate (P less than 0.01, P less than 0.002, respectively). Our results suggest that for infragenicular femoropopliteal bypass grafting where full length in-situ vein graft is not possible; a composite graft using PTFE with non-reversed vein is a good alternative.

Aged↗
PubMed1988

Surgical deaths.

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Aged↗
PubMed1988

Benign axillary epithelial lymph node inclusions--a histological pitfall.

We present two cases of axillary epithelial lymph node inclusions in the presence of benign and malignant breast disease. Although the presence of lymph node inclusions is well recognized at other sites in the body, their presence in the axillary nodes of women with breast disease necessitates close attention. This is particularly true in women with malignant breast disease as misinterpretation may lead to inappropriate treatment.

Adult↗
PubMed1987

Distal arterial bypass by composite grafting.

The use of non-autogenous prostheses for femorodistal grafting has been attended by relatively poor patency rates. We have attempted to improve on these disappointing results by fashioning a composite graft using expanded PTFE (GORE-TEX) and transposed non-reversed saphenous vein, placed between the femoral artery and anterior tibial artery. We report the early results using this technique in 25 critically ischaemic limbs. At 12 months, the cumulative graft patency for this group of patients was 65 per cent (mean follow-up of 19 months). Eighteen of the twenty-five limbs were saved and there was no mortality. This technique offers a useful alternative to other forms of distal grafting and appears superior to the results obtained using non-autogenous femorodistal conduits.

Aged↗
PubMed1986

The measurement of limb blood flow using technetium-labelled red blood cells.

A method for measuring blood flow below the knee during reactive hyperaemia induced by 3 min of arterial occlusion has been developed. Subjects are positioned with lower limbs within the field of view of a gamma camera and pneumatic cuffs are placed below the knees to isolate the blood and induce a hyperaemic response. The remaining blood pool is labelled with 99Tcm-labelled red cells. Blood flows have been derived from the initial gradients of time-activity curves and from equilibrium blood sampling. The technique has been validated using a tissue-equivalent leg phantom and peristaltic pump. The method has been applied to a small group of patients with peripheral vascular disease and to normal controls. The mean value (+/- SD) of limb perfusion for normal controls was found to be 16.4 +/- 3.0 ml/100 ml/min and for patients with intermittent claudication was 5.1 +/- 2.6 ml/100 ml/min. Flow measurements are found to correlate with clinical findings and with symptoms. Reproducibility (established by repeated measurements) is high. The method is well tolerated even by patients suffering from rest pain.

Arterial Occlusive Diseases↗
PubMed1985

Deranged liver blood flow patterns in the detection of liver metastases.

Hepatic flow scintigraphy has been used to evaluate 150 patients with gastrointestinal carcinoma. A normal range has been obtained on a group of 23 healthy volunteers. The flow scintigraphic findings have been correlated with the presence of metastases at the time of primary surgical therapy. The group of patients with livers ostensibly clear of metastases have been followed up over a one-year period. At one year the specificity of the investigation is 72 per cent with a sensitivity of 96 per cent. We conclude that flow scintigraphy is capable of not only detecting established hepatic metastases, but will also identify patients harbouring occult metastatic disease.

Gastrointestinal Neoplasms↗
PubMed1985

Phase II trial of epirubicin in gastric cancer.

Patients with advanced inoperable or recurrent adenocarcinoma of the stomach received an iv bolus of epirubicin (75 mg/m2) every 3 weeks. Partial responses were observed in four of 24 evaluable patients (17%). Treatment was generally well tolerated; a drop in left ventricular ejection fraction was observed in one patient who had received 450 mg/m2 of epirubicin.

Adenocarcinoma↗