Antioxidant effects of aminosalicylates and potential new drugs for inflammatory bowel disease: assessment in cell-free systems and inflamed human colorectal biopsies

BACKGROUND: The therapeutic efficacy of 5-aminosalicylic acid in inflammatory bowel disease may be related to its antioxidant properties. AIM: To compare in vitro the antioxidant effects of conventional drugs (5-aminosalicylic acid, corticosteroids, metronidazole), with new aminosalicylates (4-aminosalicylic acid, balsalazide) and other potential therapies (ascorbate, N-acetylcysteine, glutathione, verapamil). METHODS: Compounds were assessed for efficacy in reducing the in vitro production of reactive oxygen species by cell-free systems (using xanthine/xanthine oxidase, with or without myeloperoxidase) and by colorectal biopsies from patients with ulcerative colitis using luminol-amplified chemiluminescence. RESULTS: 5-aminosalicylic acid and balsalazide were more potent antioxidants than 4-aminosalicylic acid or N-acetyl-5-aminosalicylic acid in cell-free systems. 5-aminosalicylic acid (20 mM) and balsalazide (20 mM) inhibited rectal biopsy chemiluminescence by 93% and 100%, respectively, compared with only 59% inhibition by 4-aminosalicylic acid (20 mM). Hydrocortisone, metronidazole and verapamil had no significant effect on chemiluminescence in any system. Ascorbate (20 mM) inhibited chemiluminescence by 100% in cell-free systems and by 60% in rectal biopsies. N-acetyl cysteine (10 mM), and both oxidized and reduced glutathione (10 mM), completely inhibited chemiluminescence in cell-free systems, but not with rectal biopsies. CONCLUSIONS: The antioxidant effects of compounds varies between cell-free systems and inflamed colorectal biopsies. The effect of drugs on the chemiluminescence produced by these two assay systems is useful for screening potentially new antioxidant treatments for inflammatory bowel disease. Ascorbate seems worth further study as a novel therapy.     

The shape up challenge: a community-based worksite exercise competition

PURPOSE: To assess organizational and employee participation during three community-wide worksite exercise competitions in two communities. DESIGN: A one-group, posttest-only design was used. Lack of controls, exercise baseline, and the short-term nature of the interventions were limitations. SETTING: The Minnesota Heart Health Program conducted annual exercise campaigns between 1982 and 1989 within three intervention communities to reduce behavioral risk for cardiovascular disease. The Shape Up Challenge was a worksite exercise competition designed, in conjunction with other campaign activities, to increase levels of physical activity. SUBJECTS: A total of 119 participating companies in two Minnesota communities, and 17,626 employees within these worksites, composed the subjects in this study. INTERVENTION: Eligible worksites were invited to participate in a month-long competition during which employees recorded minutes spent daily in aerobic activities. Incentives were established to promote intragroup cooperation and intergroup competition. Companies competed for awards that were based on average minutes of exercise per employee versus per participant. MEASURES: Numbers of companies recruited and participating, campaign activities, minutes of exercise, and costs were recorded on implementation logs. Companies completed surveys describing business type, number and sex of employees, existing health promotion programs, and perceived benefits of participation. RESULTS: Of the 365 companies invited to participate, 33% participated (range 15% to 50%). Participating companies were more likely than nonparticipating companies to offer other health promotion programs and perceived greater benefits from participation. Women and smaller companies had significantly greater participation rates than men and larger companies. Average employee participation rates ranged from as high as 84% in smaller organizations to as low as 16% as organization size increased. CONCLUSIONS: Community-based worksite exercise competitions appear to be a viable strategy for promoting employee exercise, particularly in smaller companies. Group-based contingencies applied in natural work units may facilitate employee participation. Further research is needed to assess the relative efficacy of this approach, compare alternative incentives, and identify strategies to enhance exercise maintenance after the intervention has ceased.     

Luteinizing Hormone-Releasing Hormone Neurons which are R-etrogradely Labeled After Peripheral Fluoro-Gold Administration in the Male Ferret

This study identified luteinizing hormone-releasing hormone (LHRH)-producing neurons which have access to fenestrated capillaries in prepubertal male European ferrets. Fluoro-Gold was injected intraperitoneally to retrogradely label neurons with terminals outside the blood-brain barrier. LHRH neurons were identified by immunofluorescence using a secondary antibody tagged with tetramethylrhodamine isothiocyanate. Cell bodies which demonstrated both tetramethylrhodamine isothiocyanate and Fluoro-Gold fluorescence were defined as LHRH-producing neurons with axon terminals in regions containing fenestrated capillaries. The total number and neuroanatomical distribution of immunopositive (LHRH +) cells concurred with previous studies in the ferret in which cell bodies were diffusely distributed from rostral forebrain through caudal diencephalon, with approximately 70% of the LHRH + cell bodies located in retrochiasmatic hypothalamus. In the present study, an average of 59.8% of all LHRH+ neuronal perikarya also contained Fluoro-Gold. The majority of Fluoro-Gold filled LHRH+ neurons demonstrated only faint to moderate amounts of Fluoro-Gold when compared to other Fluoro-Gold filled neurosecretory neurons. This limited uptake of Fluoro-Gold may be due to a relative inactivity of LHRH neurons projecting outside the blood-brain barrier. Double-labeled LHRH + neurons were dispersed throughout the entire population of LHRH+ cell bodies and no apparent nuclear groups of double-labeled neurons were found. This observation suggests that the LHRH+ neurons responsible for neurosecretion into the median eminence coexist with the LHRH+ neurons responsible for intracerebral neurotransmission or neuromodulation. One distinguishable population of LHRH + neurons was consistently observed in all the brains. Only 26% of total LHRH+ perikarya within the caudal arcuate nucleus contained Fluoro-Gold, while at least 50% of LHRH+ neurons in other structures, including the rostral arcuate nucleus, contained Fluoro-Gold. Thus, in the prepubertal male ferret, the majority of LHRH cell bodies located in the caudal arcuate nucleus may be differentially regulated and/or involved in non-neuroendocrine functions.     

Intraoperative radiation therapy for carcinoma of the gallbladder

The recognition of a high incidence of local failure following surgical management of adenocarcinoma of the gallbladder has led to the use of adjuvant radiation therapy. In order to deliver higher doses to the gallbladder bed, intraoperative radiation therapy (IORT) has been used both with and without external beam radiation.The experience to date is reviewed. Ten patients have been treated, all of whom had either gross residual or unresected disease. The median survival for the group was approximately 1 year. There were no long-term survivors. The IORT did not contribute to the overall morbidity.Because of the limited number of patients and the advanced nature of the disease, the role of IORT in the management of gallbladder carcinoma has yet to be determined. The utility of this modality will most likely reside in the treatment of minimal residual disease at the time of cholecystectomy rather than in the palliative treatment of unresectable tumors.

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Resumen El reconocimiento de la elevada tasa de falla local en el tratamiento del adenocarcinoma de la vesícula biliar, ha motivado el uso de radioterapia adyuvante. Con el objeto de administrar altas dosis de irradiación al lecho de la vesícula billiar, se ha utilizado la radioterapia intraoperatoria (RTIO) con y sin irradiación externa.Se revisa la experiencia hasta la fecha. Diez pacientes han sido tratados, todos con enfermedad macroscópica residual o no resecable. La sobrevida media para el grupo fue de aproximadamente un año; no hay sobrevivientes a largo plazo. La RTIO no contribuyó a la morbilidad global.Debido al limitado número de pacientes y a lo avanzado de la enfermedad, el rol de la RTIO está aun por determinar. La utilidad de esta modalidad muy posiblemente habrá de residir en el tratamiento de enfermedad residual miima en el momento de la colecistectomiá, más qu en el tratamiento paliativo de tumores no resecables.

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Résumé Reconnaître la fréquence importante des échecs locaux à la suite du traitement chirurgical de l'adénocarcinome de la vésicule a amené à ajouter la radiothérapie. Pour pouvoir donner des doses plus importantes au lit de la vésicule, l'irradiation peropératoire (IP) a été administrée à la fois avec et sans irradiation externe. L'expérience à ce jour a été passée en revue. Dix patients ont été traités qui avaient soit une grosse tumeur résiduelle soit un cancer non réséqué. La survie moyenne du groupe était d'un an à peu près. Il n'y a eu aucun survivant à long terme. L'IP n'a rien changé à la mortalité globale. Compte tenu du nombre limité des patients et de la nature avancée de la maladie, le rôle de l'IP dans le traitement du cancer de la vésicule reste à déterminer. La valeur de l'IP sera probablement de traiter la petite tumeur résiduelle au moment de la cholécystectomie plutôt que les tumeurs non résécables.

     

The inexhaustible beta cell.

Repeated intensive pancreatic beta-cell stimulation was carried out in 42 subjects, comprising 22 normal controls, 10 mild to "severe" maturity-onset diabetics, and 10 chronic pancreatitis patients. Each subject received 75 gm. oral glucose twice and 1 mg. glucagon plus 0.5 gm. tolbutamide intravenously three times at short intervals. Each of the three combined stimuli caused almost equivalent marked spikes of insulin release in all experimental groups. The total calculated output of insulin was equivalent to the total daily insulin output in normal subjects. Pancreatitics and those with severe diabetes (fasting blood sugar greater than 120 mg./100 ml.) had qualitatively similar but a quantitatively smaller response. Those with mild diabetes were similar to the normal subjects but had an exaggerated response to the second oral glucose dose, suggesting overactivity of the enteroinsular axis. Despite the inordinate insulin levels, hypoglycemia did not occur.     

An audit of outcome of adjuvant post-operative radiotherapy for 52 women with stage II carcinoma of the endometrium

A retrospective review was undertaken of the medical records of 52 women with stage II carcinoma of the endometrium who received adjuvant radiotherapy following surgery. The information was obtained from medical notes and a hospital database. Actuarial disease-free survival was 68% at 5 years for those women with stage IIA disease, and 70% at 5 years for those women with stage IIB disease. 6 of the women (11.5%) had side effects from treatment. In contrast to the literature, the only statistically significant prognostic factor in this study was histological differentiation; patients with poorly differentiated tumours fared worse (p = 0.05). This may indicate that a greater number than 52 women is needed to demonstrate weaker prognostic factors such as substage. A larger review is being undertaken of the remaining women recorded on the database, with stage I, III and IV disease.     

Cyclical Etidronate Therapy for Prevention of Postmenopausal Bone Loss: A 1-Year Open-Label Follow-Up Study

The objective of this study was to evaluate whether the pharmacological activity of cyclical etidronate therapy is sustained beyond the dosing period. A group of 121 postmenopausal women who had completed a 2-year, double-blind, placebo-controlled parallel study with etidronate or placebo (400 mg/day for 14 days every 3 months) and calcium agreed to participate in a 1-year open-label follow-up study to evaluate the effect of discontinuing etidronate treatment. Fifty-nine subjects in the former etidronate group and 62 in the placebo group received 500 mg/day of elemental calcium; 54/59 and 58/62 subjects, respectively, completed the study. Outcomes of the study were bone mineral density (BMD), measured by dual energy X-ray absorptiometry (DXA), and biochemical markers of bone turnover (urinary deoxypyridinoline/creatinine and serum osteocalcin). To determine whether there was a residual effect of previous therapy we compared mean percentage changes from baseline (year 0) to year 3 for both spinal and femoral neck BMD and markers of bone turnover in the former cyclical etidronate and placebo groups. To evaluate the carryover effect of treatment we compared the percent change from year 2 to year 3 for the same variables. Mean percentage change (SEM) from year 2 to year 3 for spinal BMD in the former cyclical etidronate group was −2.87% (0.48%) versus −0.99% (0.36%) in the placebo group (P= 0.0022). In the femoral neck, the BMD changes were −0.86% (0.42%) versus −1.01% (0.41%) (NS). Biochemical markers increased within 6 months toward baseline levels. Mean percentage changes from baseline (year 0) in both spinal and femoral neck BMD were significantly different between groups 1 year after treatment discontinuation. No differences between groups were maintained in deoxypyridinoline and osteocalcin. It is concluded that following withdrawal of cyclical etidronate therapy bone loss resumes at a normal and moderately accelerated rate in the proximal femur and lumbar spine, respectively. A positive effect on BMD at both cortical and trabecular sites is maintained for 1 year after treatment withdrawal. Received: 8 May 1999 / Accepted: 10 December 1999