Recombinant human erythropoietin attenuates weight loss in a murine cancer cachexia model

Background Within hypoxic tumor regions anaerobic dissimilation of glucose is the sole source of energy generation. It yields only 5% of the ATP that is normally gained by means of oxidative glucose catabolism. The increased need for glucose may aggravate cancer cachexia. We investigated the impact of recombinant human erythropoietin (RhEPO) and increased inspiratory oxygen concentrations on weight loss in tumor-bearing mice.Methods Fragments of the murine C26-B adenocarcinoma were implanted in 60 BALB/c-mice. The mice were divided into four groups and assigned to: (A) no treatment; (B) RhEPO- administration (25 IU daily from day 1–11, three times per week from day 12); (C) RhEPO and 25% oxygen; and (D) RhEPO and 35% oxygen. Three control groups of four healthy mice each received the same treatment as groups A, B, and D, respectively. Hematocrit and hemoglobin levels, tumor volume, and body weight were monitored. At day 17 the experiment was terminated and the serum lactate concentration was measured. The tumors were excised and weighed and, for each mouse, the percentage weight loss was calculated. The impact of tumor weight and the treatments on lactate concentration and weight loss was evaluated.Results Significant positive correlations were found between tumor weight and lactate concentration and between tumor weight and percentage weight loss. In the mice with the largest tumors, RhEPO displayed a significant weight loss-reducing effect, and a significant negative correlation was found between hemoglobin concentration and weight loss. An oxygen-rich environment did not appear to influence weight loss.Conclusion Anaerobic glycolysis in a growing C26-B tumor is related to weight loss. RhEPO administration results in a reduction of the percentage weight loss; this effect is probably mediated by an increased hemoglobin concentration.This study was financially supported by a grant from Ortho Biotech, a division of Janssen Cilag, Tilburg, the Netherlands     

Randomized controlled trial of biofeedback for fecal incontinence

BACKGROUND & AIMS: Behavioral treatment (biofeedback) has been reported to improve fecal incontinence but has not been compared with standard care. METHODS: A total of 171 patients with fecal incontinence were randomized to 1 of 4 groups: (1) standard care (advice); (2) advice plus instruction on sphincter exercises; (3) hospital-based computer-assisted sphincter pressure biofeedback; and (4) hospital biofeedback plus the use of a home electromyelogram biofeedback device. Outcome measures included diary, symptom questionnaire, continence score, patient's rating of change, quality of life (short-form 36 and disease specific), psychologic status (Hospital Anxiety and Depression scale), and anal manometry. RESULTS: Biofeedback yielded no greater benefit than standard care with advice (53% improved in group 3 vs. 54% in group 1). There was no difference between the groups on any of the following measures: episodes of incontinence decreased from a median of 2 to 0 per week (P < 0.001). Continence score (worst = 20) decreased from a median of 11 to 8 (P < 0.001). Disease-specific quality of life, short-form 36 (vitality, social functioning, and mental health), and Hospital Anxiety and Depression scale all significantly improved. Patients improved resting, squeeze, and sustained squeeze pressures (all P < 0.002). These improvements were largely maintained 1 year after finishing treatment. CONCLUSIONS: Conservative therapy for fecal incontinence improves continence, quality of life, psychologic well-being, and anal sphincter function. Benefit is maintained in the medium term. Neither pelvic floor exercises nor biofeedback was superior to standard care supplemented by advice and education.     

Relationship of small bowel motility to ileoanal reservoir function.

Some patients with an ileoanal reservoir have a high defecation frequency, despite a good anatomical result and the absence of pouchitis. This study aimed to determine whether variation in function is related to a difference in small bowel motility proximal to the reservoir and if small bowel motility is propagated into the reservoir. Ambulatory small bowel and reservoir motility was studied for 24 hours in five patients with good function (median bowel frequency 4 per day, range 3-6) and seven subjects with poor function (median bowel frequency 12 per day, range 10-20). Five solid state pressure sensors were positioned in the small bowel and one in the reservoir. During the fasting nocturnal period (2300-0800 h), patients with poor function had a median of 10 (range 5-13) migrating motor complexes (MMC), significantly greater (p = 0.03) than the corresponding median number of 3 (range 2-7) in patients with good function. A total of 120 MMCs were observed in the whole series of 12 patients. Of these only two were propagated from the small bowel into the reservoir. Discrete clustered contractions were not propagated into the reservoir, although prolonged propagated contractions did pass into the reservoir in one patient. Patients with poor function had similar 24 hour stool output and radiological reservoir size to those with good function, but the median maximum tolerated volume on reservoir distension was 290 ml (range 160-450) for patients with poor function compared with 475 ml (range 460-550) for patients with good function (p = 0.005). Small bowel motility proximal to the reservoir bears an important relationship to pouch function and defecation frequency. Propagation of coordinated proximal small intestinal motility into the reservoir is rare.     

Prospective evaluation of intestinal homing memory T cells in ulcerative colitis

BACKGROUND: Intestinal homing (beta7+) memory T cells reflect the mucosal environment in which they were primed. We hypothesized that prospective assessment of cytokine production by intestinal homing (beta7+) memory T cells in ulcerative colitis patients followed from remission to early relapse may elucidate shifts in cytokine production relevant to the mucosal environment associated with the early phase of inflammation. METHODS: Twelve patients with frequently relapsing ulcerative colitis (> or = 2 relapses in the previous 12 months) were recruited in remission and followed prospectively until relapse. Antibody labeling of whole blood and flow cytometry were used to identify beta7+ cells and beta7- populations within CD3+CD45RA- leukocytes. Production of cytokines (IFN-gamma, TNF-alpha, IL-2, IL-10, TGF-beta, and IL-4) was determined by intracellular labeling. RESULTS: Early relapse of ulcerative colitis was associated with a shift of T cells from the naive to the memory T cell pool, and further the ratio of beta7+:beta7- memory T cells was significantly reduced at relapse (p < 0.01). A greater proportion of intestinal homing beta7+ memory T cells produced IL-4 (p < 0.02) and TNF-alpha (p < 0.05) at disease relapse compared with remission. Non-intestinal homing beta7- memory T cells also showed a tendency toward an increased production of TH1 and TH2 cytokines. CONCLUSIONS: The earliest phase of intestinal inflammation in ulcerative colitis patients is associated with an increase in both TH1 (TNF-alpha and TH2 (IL-4) cytokines by intestinal homing beta7+ memory T cells. These data support the principles of targeting lymphocyte trafficking as therapies in ulcerative colitis.     

Observation on the characteristics of stimulated defaecation in severe idiopathic constipation

A combined manometric and radioisotope study is described which was designed to investigate the motility characteristics of induced defaecation in the colon, rectum and anal canal, in patients with severe constipation. Five women with severe idiopathic constipation, aged 30–45 years, were studied. A multiple channel water-perfused manometric tube was placed colonoscopically into either the whole colon or left colon to monitor pressure activity. In two whole-colon studies, 5.5 MBq ¹¹¹In DTPA and later 9 MBq ^99mTc DTPA were instilled into the colon to monitor the transit of colonic contents in response to two separate stimuli. Motor activity was initiated on both occasions by intraluminal instillation of 5.5 mg bisacodyl. In the whole-colonic studies a right colonic stimulus initiated multiple high-pressure peristaltic waves which traversed the entire length of the colon. The bowel was then refractory to a second stimulus at the splenic flexure. In the five left colonic studies, a stimulus at the splenic flexure produced high-pressure peristaltic waves which proceeded distally, and which included a rise in rectal pressure. The anal canal relaxed simultaneously with the onset of peristalsis high in the left colon, and remained relaxed until the pressure wave reached the anus and bowel content had been expelled. In both types of study high-pressure waves corresponded to the effective transport of radioisotope. The constipated patients showed a coordinated motor response to the stimulus. The passage of flatus coincided with a simultaneous pressure rise in the distal colon and rectum, together with anal relaxation. These findings confirm previous observations that the defaecation induced by a luminal stimulant consists of colonic peristalsis, rectal contraction, and early anal relaxation. The ability to generate this sequence of motor activity is preserved in patients with severe idiopathic constipation.

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Résumé Une manométrie combinée à une étude par radioisotopes est décrite qui fût établie pour étudier les caractéristiques de la motilité de la défécation provoquée dans le colon, le rectum et le canal anal chez des patients avec une constipation sévère. 5 femmes avec une constipation idiopathique sévère, âgées de 30 à 45 ans, ont été étudiées. Une sonde manométrique à plusieurs canaux perfusées par de l'eau, a été placée sous coloscopie soit dans tout le colon, soit dans le colon gauche pour enregistrer les activités de pressions. Dans deux études complètes du colon, 5,5 MBq In-111 DTPA et plus tard 9 MBq 99m-Tc DTPA ont été instillés dans le colon afin d'enregistrer le transit du contenu colique en réponse à 2 stimulis séparés. L'activité motrice a été déclenchée dans les deux cas par l'instillation intra-luminale de 5,5 mg de Bisacodyl. Dans les études portant sur tout le colon, un stimulus dans le colon droit provoquait de multiples ondes péristaltiques de haute pression qui traversaient la totalité du colon. L'intestin était ensuite réfractaire à un second stimulus à l'angle splénique. Dans les 5 études portant sur le colon gauche, une stimulation au niveau de l'angle splénique provoquait des valves péristaltiques de haute pression qui se propageaint de façon distale et provoquaient une augmentation de la pression rectale. Le canal anal se relâchait simultanément avec le début du péristaltisme dans le colon gauche, et demeurait relâché jusqu'à ce que l'onde de pression atteigne l'anus et que le contenu intestinal ait été expulsé. Dans les deux types d'études les ondes de haute pressions correspondaient à un transport effectif de radioisotopes. Les patients constipés montraient une réponse motrice coordonnée aux stimulus. Le passage de gaz coincidait avec une augmentation simultanée de la pression dans le colon distal et le rectum associée a un relâchement anal. Ces résultats confirment les observations précédentes que la défécation provoquée par un stimulant intra-luminal est due à un péristaltisme colique, une contraction rectale et un relâchement anal précoce. La possibilité de provoquer cette séquence motrice est conservée chez les patients atteints de constipation idiopathique sévère.

     

Mechanical properties of carotid arteries from DOCA hypertensive swine

Carotid arteries from control and deoxycorticosterone acetate (DOCA) hypertensive swine were examined for alterations in structure and in contractile properties. Vessels were excised 7 weeks after subcutaneous implantation of the steroid and subsequent elevation in mean arterial pressure from 102 to 133 mm Hg. The carotid media was 1.8 times thicker in arteries from hypertensive animals than in arteries from control animals. This enlargement was associated with an increase in muscle mass, as the fraction of the media composed of smooth muscle cells remained unchanged. Maximal active stress induced by several agonists normalized for cell cross-sectional area was unaltered. No change was observed in sensitivity or maximal response to norepinephrine, histamine, or KCl depolarization. Isotonic shortening rates were also comparable, as was the time course of shortening velocity to a constant afterload during tonic contractions. It is concluded that an enlargement of the carotid media develops in this model of hypertension. However, this response is not associated with detectable alterations in contractile system function.