Fibre-supplemented tube feeding in the hospitalised elderly

OBJECTIVES: To evaluate the effect of fibre supplementation in enteral feeding on bowel function in hospitalised geriatric patients, and to assess its metabolic and nutritional efficiency. DESIGN: Prospective randomised controlled trial with stratification for diabetes. SETTING: Department of Geriatrics at the University of Antwerp. SUBJECTS: During 30 months (January 2000-June 2002) every hospitalised patient requiring tube feeding was assessed for eligibility (n = 183). Finally 172 patients (19% diabetics) were randomised. METHODS: An enteral nutritional regimen consisting of 30 kcal/kg in 2000 ml with a calorie/nitrogen ratio of 156 with or without fibre was instituted. At weekly intervals, stool output was qualitatively evaluated by recording frequency, volume (small <1/2 cup, large >1/2 cup) and consistency (solid-formed, soft-pasty or liquid-watery). Nutritional and metabolic effects were evaluated through laboratory analysis. RESULTS: Overall mortality was 24% with a trend for excess mortality in diabetic patients (33.3% versus 21.6% in non-diabetics; P = 0.176). There was no difference in duration of feeding between the fibre group (27.5 days; 95% CI = 19.1-35.9) and the no fibre group (27.9 days; 95% CI = 20.2-35.5). In the fibre-supplemented group, stool frequency was lower (4.1 per week; 95% CI = 3.7-4.6) than in controls (6.3 per week; 95% CI = 5.6-6.9). Qualitatively, stool consistency was higher (P < 0.001) but no difference in volume was noted. There were no differences in final laboratory parameters between groups. CONCLUSIONS: Fibre supplementation improved bowel function with reduced stool frequency and more solid stool consistency. It did not affect the nutritional efficiency of enteral feeding in hospitalised geriatric patients. Diabetes may be a risk factor for mortality in malnourished patients requiring tube feeding.     

Nijmegen breakage syndrome gene (NBS1) is not the tumor suppressor gene at 8q21.3 involved in colorectal carcinoma

Genetic instability is characteristic of cancer cells, both at the chromosomal level (e.g., aneuploidy, aneusomy, translocations), and at the sequence level (e.g., microsatellite instability). Colorectal cancers (CRCs) can be divided into two groups: tumors of the proximal colon, where microsatellite instability is frequent and chromosomal aberrations are rare, and tumors of the distal colon, where microsatellite instability is less frequent and chromosomal aberrations are common. Constitutional chromosomal instability is a hallmark of the Nijmegen breakage syndrome (NBS), a disorder in which the NBS1 gene is mutated. In a previous study, we found an elevated frequency of allelic imbalance (AI) at the 8q21.3 NBS1 locus in proximal, though not distal CRCs. This result suggested that the loss of NBS1 might contribute to the genetic instability, and thus the malignant progression, of proximal CRC. We therefore sequenced the 16 exons of the NBS1 gene in all cases where we had observed AI. Of the 29 cases, none showed any sequence anomaly, although several polymorphisms were found. We also studied markers flanking the recently described Rad54B gene, which is a member of the Rad52 epistasis group to which NBS1 itself belongs. Mutations of this gene, located a few cM distal to NBS1, have been found in colorectal cancer and in primary lymphomas, and it may thus be the target of AI at 8q21. We found that AI at Rad54B was not frequent, and none was observed in cases showing AI at NBS1.     

Simultaneous measurement and integrated analysis of analgesia and respiration after an intravenous morphine infusion

BACKGROUND: To study the influence of morphine on chemical control of breathing relative to the analgesic properties of morphine, the authors quantified morphine-induced analgesia and respiratory depression in a single group of healthy volunteers. Both respiratory and pain measurements were performed over single 24-h time spans. METHODS: Eight subjects (four men, four women) received a 90-s intravenous morphine infusion; eight others (four men, four women) received a 90-s placebo infusion. At regular time intervals, respiratory variables (breathing at a fixed end-tidal partial pressure of carbon dioxide of 50 mmHg and the isocapnic acute hypoxic response), pain tolerance (derived from a transcutaneous electrical acute pain model), and arterial blood samples were obtained. Data acquisition continued for 24 h. Population pharmacokinetic (sigmoid Emax)-pharmacodynamic models were applied to the respiratory and pain data. The models are characterized by potency parameters, shape parameters (gamma), and blood-effect site equilibration half-lives. All collected data were analyzed simultaneously using the statistical program NONMEM. RESULTS: Placebo had no systematic effect on analgesic or respiratory variables. Morphine potency parameter and blood-effect site equilibration half-life did not differ significantly among the three measured effect parameters (P > 0.01). The integrated NONMEM analysis yielded a potency parameter of 32 +/- 1.4 nm (typical value +/- SE) and a blood-effect site equilibration half-life of 4.4 +/- 0.3 h. Parameter gamma was 1 for hypercapnic and hypoxic breathing but 2.4 +/- 0.7 for analgesia (P < 0.01). CONCLUSIONS: Our data indicate that systems involved in morphine-induced analgesia and respiratory depression share important pharmacodynamic characteristics. This suggests similarities in central mu-opioid analgesic and respiratory pathways (e.g., similarities in mu-opioid receptors and G proteins). The clinical implication of this study is that after morphine administration, despite lack of good pain relief, moderate to severe respiratory depression remains possible.     

MR imaging features in Marinesco-Sjögren syndrome: severe cerebellar atrophy is not an obligatory finding

BACKGROUND AND PURPOSE: Cerebellar atrophy is considered the most prominent neuroradiologic finding in Marinesco-Sj?gren syndrome (MSS). Our purpose was to investigate this neuroradiologic feature in a series of patients with MSS. METHODS: Five patients with MSS (age range, 5-19 years) underwent native MR imaging of the brain. The findings were assessed with particular attention to the cerebellum and the supratentorial structures. RESULTS: Only two patients had slight cerebellar atrophy; the cerebellum was normal in size and configuration in the other patients. Additional supratentorial findings were present in some of the patients, with an apparently small anterior pituitary gland in two and the absence of the posterior pituitary bright spot in three of the patients. CONCLUSION: Cerebellar atrophy is not an obligatory finding in MSS, and almost normal cranial MR imaging results are compatible with the diagnosis. Morphologic changes of the pituitary gland seem to be common in patients with MSS and are not associated with endocrine dysfunction.     

A randomized, double-blind, placebo-controlled pilot study of IV morphine-6-glucuronide for postoperative pain relief after knee replacement surgery

OBJECTIVES: To determine the dose-response effect of intravenous morphine-6-glucuronide (M6G) on acute postoperative pain. METHODS: Patients undergoing knee replacement surgery under spinal anesthesia were randomly assigned to 1 of 4 single intravenous M6G doses, 0 (placebo), 10, 20, or 30 mg/70 kg, administered 150 minutes after the spinal anesthetic was given. Analgesic effects were evaluated by determining the cumulative patient controlled analgesia (PCA) morphine dose, consumed over a 12 and 24 hours period, after the initial dose of M6G. For pain assessments, a 10 cm visual analog scale was used. RESULTS: Data from 41 patients were evaluated (n=10, 10, 10, and 11 in the 0, 10, 20, and 30 mg M6G groups). Only at the highest M6G dose (30 mg/70 kg), morphine PCA consumption was significantly less compared with placebo: over the first 12 postoperative hours mean PCA morphine consumption was 3.0+/-2.0 mg/h after placebo and 1.4+/-0.5 mg/h after 30 mg M6G (P=0.03); over the first 24 h mean PCA morphine consumption was 2.5+/-2.1 mg after placebo and 1.0+/-0.4 mg after 30 mg M6G (P=0.04) (mean+/-SD). Visual analog scale values were similar across all groups during these time periods. DISCUSSION: The analgesic effect of M6G in postoperative pain was demonstrated with 30 mg/70 kg M6G superior to placebo. At this dose, M6G has a long duration of action as determined by a reduction in the use of morphine PCA over 12 and 24 hours.     

Simultaneous Measurement and Integrated Analysis of Analgesia and Respiration after an Intravenous Morphine Infusion

Background: To study the influence of morphine on chemical control of breathing relative to the analgesic properties of morphine, the authors quantified morphine-induced analgesia and respiratory depression in a single group of healthy volunteers. Both respiratory and pain measurements were performed over single 24-h time spans.

Methods: Eight subjects (four men, four women) received a 90-s intravenous morphine infusion; eight others (four men, four women) received a 90-s placebo infusion. At regular time intervals, respiratory variables (breathing at a fixed end-tidal partial pressure of carbon dioxide of 50 mmHg and the isocapnic acute hypoxic response), pain tolerance (derived from a transcutaneous electrical acute pain model), and arterial blood samples were obtained. Data acquisition continued for 24 h. Population pharmacokinetic (sigmoid Emax)-pharmacodynamic models were applied to the respiratory and pain data. The models are characterized by potency parameters, shape parameters ([gamma]), and blood-effect site equilibration half-lives. All collected data were analyzed simultaneously using the statistical program NONMEM.

Results: Placebo had no systematic effect on analgesic or respiratory variables. Morphine potency parameter and blood-effect site equilibration half-life did not differ significantly among the three measured effect parameters (P > 0.01). The integrated NONMEM analysis yielded a potency parameter of 32 +/- 1.4 nm (typical value +/- SE) and a blood-effect site equilibration half-life of 4.4 +/- 0.3 h. Parameter [gamma] was 1 for hypercapnic and hypoxic breathing but 2.4 +/- 0.7 for analgesia (P < 0.01).     

Mechanism-based pharmacokinetic-pharmacodynamic modeling of the antinociceptive effect of buprenorphine in healthy volunteers

BACKGROUND: The objective of this investigation was to characterize the pharmacokinetic-pharmacodynamic relation of buprenorphine's antinociceptive effect in healthy volunteers. METHODS: Data on the time course of the antinociceptive effect after intravenous administration of 0.05-0.6 mg/70 kg buprenorphine in healthy volunteers was analyzed in conjunction with plasma concentrations by nonlinear mixed-effects analysis. RESULTS: A three-compartment pharmacokinetic model best described the concentration time course. Four structurally different pharmacokinetic-pharmacodynamic models were evaluated for their appropriateness to describe the time course of buprenorphine's antinociceptive effect: (1) E(max) model with an effect compartment model, (2) "power" model with an effect compartment model, (3) receptor association-dissociation model with a linear transduction function, and (4) combined biophase equilibration/receptor association-dissociation model with a linear transduction function. The latter pharmacokinetic-pharmacodynamic model described the time course of effect best and was used to explain time dependencies in buprenorphine's pharmacodynamics. The model converged, yielding precise estimation of the parameters characterizing hysteresis and the relation between relative receptor occupancy and antinociceptive effect. The rate constant describing biophase equilibration (k(eo)) was 0.00447 min(-1) (95% confidence interval, 0.00299-0.00595 min(-1)). The receptor dissociation rate constant (k(off)) was 0.0785 min(-1) (95% confidence interval, 0.0352-0.122 min(-1)), and k(on) was 0.0631 ml . ng(-1) . min(-1) (95% confidence interval, 0.0390-0.0872 ml . ng(-1) . min(-1)). CONCLUSION: This is consistent with observations in rats, suggesting that the rate-limiting step in the onset and offset of the antinociceptive effect is biophase distribution rather than slow receptor association-dissociation. In the dose range studied, no saturation of receptor occupancy occurred explaining the lack of a ceiling effect for antinociception.