On-off study of manganese administration to adult patients undergoing home parenteral nutrition: new indices of in vivo manganese level.

BACKGROUND: Recently, there have been reports that magnetic resonance imaging (MRI) reveals high-intensity T1-weighted images (HI) in the basal ganglia (especially in the globus pallidus) of patients receiving total parenteral nutrition (TPN). This finding is presumably due to excess administration of manganese. We investigated the reversibility and reproducibility of these changes by means of an on-off manganese administration study. We also investigated the temporal relationships between the intensity of T1-weighted images (MRI intensity) and the whole-blood and plasma manganese concentrations to evaluate the potential for the MRI intensity to serve as an index of the in vivo manganese level. METHODS: Eleven adult patients undergoing home parenteral nutrition received TPN solutions containing manganese (0 or 20 micromol/d) according to an on-off design. The whole-blood and plasma manganese concentrations were determined at the same time the brain MRI was performed. RESULTS: Both the whole-blood manganese concentration and the MRI intensity in the globus pallidus changed in response to the administration and withdrawal of manganese. It took at least 5 months for HI to disappear when manganese was withdrawn, and this change was reversible and reproducible. The whole-blood manganese concentration showed strong correlations with both the MRI intensity and the T1 value (r = 0.7693, -0.7011). The MRI intensity and the T1 value showed a strong correlation (r = -0.9051). CONCLUSIONS: The whole-blood manganese concentration, the MRI intensity in the globus pallidus and the T1 value, an objective index of the MRI intensity, may be useful indices of the manganese level in the body.

Nitric oxide synthase inhibitor attenuates inflammatory lesions in the skin of zinc-deficient rats.

Skin lesions are common manifestations of zinc deficiency in humans and animals, but the pathogenic mechanisms have not been fully clarified. In the present study, a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), was given to zinc-deficient (ZD) rats to see whether it prevents or delays the occurrence of skin lesions. Weanling male rats were given free access to a ZD diet (2 mg zinc/kg) for 4 wk to induce zinc deficiency. Control rats, including pair-fed (PF) and ad libitum (AL) groups, were given a diet supplemented with zinc (50.8 mg zinc/kg. L-NAME (0.3 g/L in drinking water) was given to some ZD rats for 3 wk, starting at the second week of their ZD dieting. Dermatitis of the extremities, balanitis, stomatitis, and alopecia appeared in ZD but not in AL and PF rats. Administration of L-NAME significantly reduced the frequency of cutaneous and mucocutaneous inflammatory lesions but did not prevent alopecia in the ZD rats. Reverse transcription polymerase chain reaction showed that inducible nitric oxide synthase mRNA was expressed in the paw skin of ZD but not of AL and PF rats. Evaluation of skin microvascular permeability by the Evans blue leakage technique indicated that L-NAME administration significantly attenuated extravasation of Evans blue in the paw skin of ZD rats. Furthermore, stains positive for terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling were condensed and diffusely distributed over the epidermis, dermis, and subcutaneous tissue of paws in ZD rats. ZD rats had intense cell infiltration and parakeratosis in the paw skin. L-NAME administration effectively prevented these morphologic changes. These results demonstrate that nitric oxide synthase inhibitor ameliorates inflammatory lesions of the skin in ZD rats.

Intestinal adaptation in pediatric patients with short-bowel syndrome.

The purpose of this study is to evaluate 12 pediatric short-bowel syndrome (SBS) patients experienced at Osaka University Hospital and its affiliated hospitals and to study the intestinal length for achieving intestinal adaptation and the metabolic characteristics. The length of the residual small intestine ranged from 0 to 75 cm with an average of 47 cm and an ileocecal valve had been resected in five cases. Total parenteral nutrition (TPN) was started immediately after operation and was gradually substituted by enteral nutrition. No patient died during the follow-up period. Eight of 12 patients could be weaned from TPN with residual intestinal length of 27 to 75 cm (mean 57 cm). Four patients with the residual intestine of 0 to 45 cm (mean 22 cm) were unable to achieve intestinal adaptation. The rate of catheter-related sepsis per 1000 catheter days was 0.63. Fatty liver was detected in two cases, but no patient developed progressive liver failure. Plasma arginine and citrulline were decreased in patients who were unable to achieve intestinal adaptation. Our nutritional support program provided excellent survival for pediatric SBS patients primarily due to the low incidence of catheter-related sepsis and no episode of severe liver disease. Patients with more than 16 cm of residual intestinal length can be expected to be weaned from TPN.

Insulin-like growth factor-1 modulation of intestinal epithelial cell restitution.

After superficial intestinal injury, the mucosal integrity is reestablished by rapid migration of epithelial cells from the adjacent area in a process called restitution. Our previous study suggested that growth hormone improves intestinal healing in an experimental small bowel ulceration, mediated by insulin-like growth factor-1 (IGF-1). The aim of the present study was to assess the role of IGF-1 in mucosal epithelial restitution using an in vitro epithelial wound model. Wounds were established in confluent monolayers of the intestinal cell line, IEC-6. Migration was quantitated in the presence or absence of IGF-1 as the number of cells migrating across the wound edge. Proliferation was assessed by thymidine incorporation. IGF-1-enhanced epithelial cell migration by 2- to 2.5-fold after 12- and 24-hour treatment, respectively, the first step involved in gastrointestinal wound healing. Cell proliferation was significantly stimulated by IGF-1 as well. In addition, expression of transforming growth factor-beta (TGF-beta) mRNA was significantly enhanced in the wounded monolayers treated with IGF-1. IGF-1 receptor mRNA was found to be detectable throughout the gastrointestinal mucosa and in the intestinal epithelial cells. In conclusion, these findings suggest that IGF-1 plays an important role in reconstitution of intestinal epithelial integrity after mucosal injury.

Long-term outcome of short bowel syndrome in adult and pediatric patients.

We reviewed 12 pediatric and 18 adult patients with short bowel syndrome (SBS) from Osaka University Hospital and compared clinical characteristics between them. The length of the residual small intestine ranged from 0 to 75 cm (mean 47 cm) in pediatric patients and from 0 to 150 cm (mean 47 cm) in adult patients. In all cases, total parenteral nutrition (TPN) was started immediately after surgery and was gradually replaced by enteral nutrition. Eight pediatric patients (67%) and 4 adult patients (22%) were weaned from TPN. Residual intestinal length in these patients ranged from 27 to 75 cm (mean 57 cm) in pediatric patients and 57 to 150 cm (mean 96 cm) in adult patients. Pediatric patients with residual small intestinal lengths of 0, 16, 25, and 45 cm were not weaned from TPN. None of the adult patients with residual small intestinal length less than 40 cm could achieve complete intestinal adaptation. Five adult patients died due to liver failure (2 cases), heart failure (2 cases), or pneumonia (1 case), whereas all pediatric patients survived. The average life span of indwelling central venous catheters was 511 days and 780 days, and the rate of catheter-related sepsis per 1000 catheter days was 0.73 and 0.48 in pediatric and adult patients, respectively. Plasma levels of arginine and citrulline in patients receiving TPN were significantly decreased compared with those in patients receiving TPN without SBS both in pediatric and adult patients (p < .01). These results indicate that pediatric and adult patients with SBS can survive with TPN and enteral nutrition. The minimum remaining intestinal length necessary for complete bowel adaptation is shorter for pediatric patients than adults, suggesting better bowel adaptation in pediatric patients.

Nitric oxide synthase inhibitor attenuates intestinal damage induced by zinc deficiency in rats.

A nitric oxide synthase (NOS) inhibitor, NG-nitro-L -arginine methyl ester (L-NAME), was given to zinc-deficient (ZD) rats to determine whether it prevents the intestinal damage usually observed under these conditions. Weanling male rats were given free access to a ZD diet (2 mg zinc/kg), whereas control rats including pair-fed (PF) and ad libitum consumption (AL) groups were given a zinc-supplemented (50.8 mg zinc/kg) diet for 4 wk. Half of the ZD rats received L-NAME (0.3 g/L in drinking water) for 3 wk starting at the wk 2 of the deficient period. Plasma zinc concentration in ZD rats was significantly lower (P < 0.05) than that of AL and PF rats. Administration of L-NAME did not alter this concentration. Intestinal zinc concentration did not differ among groups. However, metallothionein-1 (MT-1) mRNA level was significantly lower in the intestine of ZD rats than in AL or PF rats. Treatment of ZD rats with L-NAME did not affect this level. Intestinal microvascular permeability evaluated by Evans blue showed significantly higher extravasation in ZD rats than in AL rats, whereas L-NAME administration inhibited the extravasation. Expression of inducible NOS mRNA was observed in intestine of ZD but not of AL or PF rats, and there was no significant difference between ZD rats, regardless of L-NAME treatment. The activity ratio of inducible NOS to total NOS in ZD rats not receiving L-NAME was significantly higher than that in AL rats or ZD rats treated with L-NAME (P < 0.05). The number of apoptotic-positive and goblet cells in intestinal villi was significantly higher in ZD rats compared with AL or PF rats. L-NAME administration in ZD rats reversed this effect. These results indicate that inhibition of NOS ameliorates zinc deficiency-induced intestinal damage in rats.

Alanyl-glutamine-supplemented parenteral nutrition increases luminal mucus gel and decreases permeability in the rat small intestine.

BACKGROUND: Effect of supplemental alanyl-glutamine in standard TPN (S-TPN) on luminal mucus gel and small intestinal permeability was investigated. METHODS: Thirty Sprague-Dawley rats were divided into group I (n = 10), receiving standard rat diet; group II (n = 10), receiving S-TPN; and group III (n = 10), receiving alanyl-glutamine-supplemented TPN for 1 week. After 1 week, fluorescein isothiocyanate (FITC)-dextran was injected into the small intestine of the rats, and they were killed. A small intestinal sample and portal blood were obtained for morphologic and functional analysis of mucus gel and intestinal permeability. RESULTS: In group II, thickness and optical density of mucus gel per millimeter serosal length of intestine were significantly lower than group I (p<.001) and were significantly higher in group III than in group II (p<.001). The number of goblet cells in the villi and in the crypt of the small intestine was significantly lower in group II than in group I (p<.001) and was significantly higher in group III than in group II (p<.001), with the exception of the villi of jejunum. Villous and crypt surface area per millimeter serosal length of intestine was significantly lower in group II than in group I (p<.001) and was significantly higher in group III than in group II (p<.001). Small intestinal permeability to FITC-dextran was significantly higher in group II than in group I (p<.001) and was significantly lower in group III than in group II (p<.001). Glucosamine synthetase level was significantly higher in group III than in group I and ileum of group II (p<.001). CONCLUSIONS: Alanyl-glutamine-supplemented TPN prevents a decrease in mucus gel and an increase in small intestinal permeability associated with S-TPN.

Optimal protein requirements during the first 2 weeks after the onset of critical illness.

OBJECTIVE: To obtain optimal protein requirements in critically ill sepsis or trauma patients during the first 2 wks after admission to the intensive care unit. DESIGN: Retrospective study. SETTING: Department of critical care medicine at a teaching hospital. PATIENTS: Immediate posttrauma patients or severely septic patients. INTERVENTIONS: In vivo neutron activation analysis was used to measure changes in total body protein over a 10-day period which began as soon as the patients were hemodynamically stable. The patients (trauma, n=18; sepsis, n=5) were divided into three groups according to the average daily protein intakes. Because the patients were overhydrated (approximately 10 L) and had variable amounts of body fat, the protein intakes were indexed to normally hydrated (corrected) fat-free mass (FFMc): Groups A, B, and C received an average of 1.1, 1.5, and 1.9 g/kg FFMc/day protein, respectively. MEASUREMENTS AND MAIN RESULTS: Overall, the average loss of total body protein was 1.2=0.7 (SD) kg. Changes in total body protein were significantly (p=.011) different between the three groups. The loss of body protein was significantly more in group A compared with groups B (p=.013) and C (p=.023). When the protein intake was increased from 1.1 g/kg FFMc/day to 1.5 g/kg FFMc/day, protein loss was halved. Further increase in protein intake up to 1.9 g/kg FFMc/day resulted in no further improvement. An intake of 1.5 g/kg FFMc/day was equivalent to 1.0 g/day/kg of body weight measured at the beginning of the study. CONCLUSIONS: Current recommended protein requirements of 1.2 to 2.0 g/kg of body weight/day are excessive if they are indexed to the body weight measured soon after the onset of critical illness. Because individual patients have varying degrees of overhydration early in the illness onset, we suggest that the intensivist should obtain information on preillness body weight and prescribe 1.2g of protein/kg body weight/day. If information is not available, 1.0g of protein/day/kg of measured body weight will give a fair approximation to optimal protein requirements.

Zinc deficiency enhances interleukin-1alpha-induced metallothionein-1 expression in rats.

This study investigated whether interleukin-1alpha-induced metallothionein gene expression is affected by zinc deficiency. Weaning male rats were fed a zinc-deficient (ZD) diet (2 mg zinc/kg) or a zinc-supplemented diet [50.8 mg zinc/kg; controls for the diet included pair-fed (PF) and ad libitum consumption groups (AL)] for 4 wk. All rats except those that served as controls for interleukin-1alpha administration, (injected with vehicle and killed at 0 h) were then injected subcutaneously with interleukin-1alpha (2 x 10(7) units/kg body wt) and killed at 3, 6, 12, 24 and 72 h after the injection. Compared with AL and/or PF rats, zinc depletion significantly reduced zinc concentrations in plasma and liver but not in kidney or intestine, and significantly reduced hepatic, renal, and intestinal metallothionein-1 mRNA levels analyzed by competitive reverse transcription-polymerase chain reaction (RT-PCR). Interleukin-1alpha injection reduced plasma zinc concentration and enhanced liver zinc concentration, but did not affect zinc levels in kidney or intestine. Metallothionein-1 mRNA was significantly elevated by interleukin-1alpha in liver, kidney and intestine of all groups; the levels in liver and kidney of ZD rats 6 h after the injection were significantly higher than those of AL or PF rats. Liver metallothionein protein levels were enhanced after interleukin-1alpha injection in both AL and ZD rats. Semiquantitative RT-PCR revealed significantly higher hepatic levels of interleukin-1 receptor type-I mRNA in ZD rats than in AL and PF rats but no differences in renal or intestinal tissues among groups before interleukin-1alpha challenge. In conclusion, zinc deficiency induces upregulation of metallothionein-1 gene expression in response to interleukin-1alpha challenge in rats.

[History of progress in nutritional assessment].

Progress in nutritional assessment is reviewed. 1) Initial period (1930-1959): The first nutritional assessment procedures were surveys designed to describe the nutritional status of populations on a national basis. The important relationship between nutritional status and health was well documented and awareness among surgeons and physicians of the importance of nutritional assessment increasing during the 1950s. Enteral nutrition techniques were established and research on parenteral nutrition started. 2) Established period (1960-1979): With the development of enteral and parenteral nutrition techniques, the determination of the nutritional status of individual patients took on new importance. New concepts and methods were devised and used in developing regions of the world and for the assessment of the nutritional status of hospitalized patients during the 1970s. 4) Developing period (after 1980): After 1980, investigators began to examine functional indices and combinations of parameters that would have prognostic value in order to determine the indications for clinical outcome. Many types of sophisticated equipment for assessing nutritional status became available and encouraged the development of a new concept of body composition. Despite the development of such new technologies, experienced clinicians were able to obtain a remarkable degree of agreement. Further education of all staff is essential in the clinical art of detecting the early and subtle changes of malnutrition.

Lock method using sodium hydroxide solution to clear occluded central venous access devices.

Occlusion of central venous access devices (CVADs) is not an uncommon problem duringlong-term parenteral nutrition. A number of techniques have been developed to deal with obstructed CVADs. This study investigated the effectiveness of the sodium hydroxide (NaOH) lock method for gradual CVAD occlusion. When a progressively declining flow was noticed, 0.1 N NaOH solution was injected into the CVAD and locked. Nineteen CVAD occlusions in 11 home parenteral nutrition patients were treated Sixteen of 19 trials cleared the occlusions, whereas 3 of 19 failed. One of the failures was due to a mechanical occlusion and the other two were able to be restored by using ethanol. There were no significant complications. The benefits of this method are: (1) a shorter treatment time and a lower dose than NaOH infusion therapy, (2) it does not require hospital admission and (3) it does not result in bursting of the catheter.

Hyaluronic acid of wound fluid in adult and fetal rabbits.

Fetal wound healing proceeds without fibrosis or scar formation in contrast to adult wound healing. The mechanisms responsible for this remarkable process are mediated in part through a fetal wound extracellular matrix rich in hyaluronic acid (HA). Polyvinylalcohol sponge (PVA) wound implants were placed pervertebrally at 24 days' gestation in fetal (N = 118) rabbits and in adult (N = 44) rabbits, and then harvested at 1, 2, 3, 4, 5, and 7 days postwounding. To analyze the fetal and adult wound matrix, the HA concentration of wound fluid within the PVA sponge was quantitated using a newly developed assay. A significantly increased (P < .05) HA deposition on days 1 through 7 in the fetal wounds was found compared with the adult wound. These observations may suggest an important physiologic role in fetal wound healing by providing a more fluid and malleable matrix. These results, coupled with earlier findings of the lack of an acute inflammatory response in the fetus, further support the hypothesis that fetal response to injury is significantly different from adult response in this prescience of an implanted PVA sponge.

Developmental changes in distribution of the mucous gel layer in rat small intestine.

The intraluminal mucous gel layer across the small intestine of rats aged 3 days, 1, 2, 4 and 6 weeks (n=10x5) was studied to investigate its postnatal development. Celloidin stabilisation of dried cryostat sections of small intestine, with the luminal contents, preserved the intraluminal mucous gel layer for staining by the periodic acid-Schiff reaction. Morphological differences in the mucous gel, between the villi of the small intestine, in rats of several postnatal ages were observed, most notably after the age of 2 weeks. The adhesive mucous gel layer, covering the intestinal epithelium in the small intestine, appears to undergo rapid development after weaning.

[Home parenteral nutrition in the elderly].

The number of elderly patients receiving home parenteral nutrition (HPN) has been increasing. This could result from several factors such as advances in HPN therapy and the natural aging of long-term older patients on HPN. Our experience shows that elderly patients receiving HPN are likely to be highly dependent on family members to supervise their HPN therapy. Therefore, indepth education of family members is essential before HPN is initiated. The important points to manage the elderly HPN patients are as follows: 1) It takes a long time for the elderly to learn the technique. 2) They often make technical mistakes. 3) In many cases, patients are not living with their children. Therefore, it is often difficult for them to support the patient's HPN therapy. 4) Nurses play an important role in giving instructions on catheter care and HPN techniques to the patient or family members.

Adhesive mucous gel layer and mucus release as intestinal barrier in rats.

BACKGROUND: Although it has been reported that total parenteral nutrition induces an increased intestinal permeability and a decreased mucous gel layer covering the intestinal epithelium, the role of mucous gel on intestinal permeability has not been well understood. We examined the in vivo effects of N-acetyl cysteine (NAC) as mucolytic agent and colchicine as suppressant of the mucus production on the intestinal transmission of fluorescein isothiocyanate dextran 70,000 (FITC-dextran). METHODS: Rats were divided into four groups. In each group, FITC-dextran (750 mg/kg) with or without NAC (3000 mg/kg) was injected into the small intestinal lumen 3 hours after intraperitoneal injection of saline or colchicine (Col, 10 mg/kg). Thirty minutes after injection of FITC-dextran, blood samples were taken from portal vein to analyze plasma fluorescein concentration by fluorescence spectrometry. Samples of small intestine were sectioned in a cryostat for fluorescence microscopy, and the identical sections were stained by periodic acid-Schiff reaction. RESULTS: Plasma FITC-dextran level in NAC group was higher than that in control group (p < .01), that in Col + NAC group was higher than that in Col group (p < .01) and that in Col + NAC group was higher than that in NAC group (p < .05). The spaces between villi were filled with mucous gel in the control and Col groups, whereas those were not entirely filled with mucous gel in NAC and Col + NAC groups. FITC-dextran and mucous gel showed complementary distribution in all rats. The villous interstitial edema was recognized in NAC group and the villi were disrupted in Col + NAC group. CONCLUSIONS: These results suggest that intestinal permeability is possibly affected not only by the mucous gel covering the intestinal epithelium but also by mucus release from goblet cells of the small intestine.

Influence of glutamine-supplemented parenteral nutrition on intestinal amino acid metabolism in rats after small bowel resection.

Glutamine (Gln)-supplemented total parenteral nutrition (TPN) has been shown to improve mucosal adaptation after massive small bowel resection (SBR); however, its influences on intestinal amino acid metabolism remain unknown. In this study, intestinal amino acid flux, circulating plasma aminogram, mucosal glutaminase activity and protein, and DNA content were measured 7 days after massive SBR in rats receiving either standard (Std) or Gln-supplemented TPN. Sham-operated rats and rats fed chow after enterectomy served as controls. The uptake of Gln and the release of citrulline (Cit) by the remaining intestine was significantly decreased, with reduced mucosal glutaminase activity after SBR in the Chow and Std-TPN groups. Glutamine supplementation resulted in significantly increased gut Gln uptake compared with Std-TPN (P < 0.01). Mucosal glutaminase activity, mucosal protein, and DNA content was also increased by Gln; however, the gut release of Cit remained unchanged (P > 0.05). The subsequent decrease in circulating arginine (Arg) in the Gln-TPN group compared with the Std-TPN group (P < 0.05) was attributed to an insufficient exogenous supply. These findings show that Gln-supplemented TPN improves mucosal growth and gut Gln uptake after SBR. However, the intestinal production of Cit, which remained low in both TPN groups, may lead to an insufficiency of endogenous Arg synthesis. Thus, both Gln and Arg may be essential amino acids after SBR.

Trace element metabolism in parenteral and enteral nutrition.

With more patients receiving artificial nutrition, i.e., TPN and EN, deficiencies of essential trace elements have appeared. Because symptomatic deficiencies might be only a small part of the abnormalities, we should recognize a much wider background of abnormal metabolism and physiology of such elements and examine their possible participation in most diseases. Measurements of biochemical indices of trace elements in these patients frequently reveal decreased levels. To prevent marginal deficiencies and maintain good balance in the body, routine administration of trace elements is therefore essential. Discussions focus on daily requirements, including the recommended doses of each trace element in PN and EN formulas. The range of different recommended doses in different countries, and the content and completeness of trace element mixtures available in these countries is a matter of concern. A consensus based on better data from patients with different clinical states is urgently required.