Biomedical subjects

L Gianotti

Publications and source records attributed to L Gianotti.

At least 19 recordsLinked to original sources

PubMed1998

Effects of beta-adrenergic agonists and antagonists on the growth hormone response to growth hormone-releasing hormone in anorexia nervosa.

BACKGROUND: In anorexia nervosa (AN), growth hormone (GH) hypersecretion and low insulin-like growth factor I (IGF-I) levels are present. It is unclear whether this is due to a peripheral GH resistance and a reduced IGF-I negative feedback on GH secretion or to a primary hypothalamic dysfunction. In AN, in contrast to normal subjects, cholinergic antagonists and agonists, whose action is somatostatin (SS)-mediated, have reduced and absent effects on the GH response to growth hormone-releasing hormone (GHRH). Since arginine, another substance acting via inhibition of SS, maintains its potentiating effect on GH secretion in AN, it has been hypothesized that somewhat specific alteration of the SS-mediated cholinergic influence may be present in this condition. To further clarify the neural control of AH secretion in AN, we evaluated the effects of beta-adrenergic agonists and antagonists, which are known to inhibit and increase, respectively, the GHRH-induced GH secretion in normal subjects. METHODS: We studied the effect of atenolol (ATE), a beta 1-adrenergic antagonist, and salbutamol (SALB), a beta 2-adrenergic agonist, on the GHRH-induced GH release in 10 patients with AN and in 10 normal age-matched women (NW). RESULTS: Basal GH levels were higher, whereas IGF-I were lower in AN than in NW. The GHRH-induced GH rise in AN was higher than that in NW. ATE significantly enhanced the GH response to GHRH in NW, but not in AN. The GH responses to GHRH after ATE pretreatment were similar in NW and in AN. The GH response to GHRH was inhibited by SALB in both NW and AN. The GH responses to GHRH after SALB pretreatment were similar in NW and AN. CONCLUSIONS: These data reveal an exaggerated somatotrope responsiveness to GHRH in AN that is not further increased by beta-adrenergic blockade, while is abolished by beta-adrenergic activation. This suggests that an impairment of beta-adrenergic influence on GH secretion is present in anorexia nervosa.

Adolescent↗

PubMed1998

Artificial nutrition after major abdominal surgery: impact of route of administration and composition of the diet.

OBJECTIVE: To evaluate the impact of the route of administration of artificial nutrition and the composition of the diet on outcome. DESIGN: Prospective, randomized, clinical trial. SETTING: Department of surgery, university hospital. PATIENTS: One hundred sixty-six consecutive patients undergoing curative surgery for gastric or pancreatic cancer. INTERVENTIONS: At operation, the patients were randomized into three groups to receive: a) a standard enteral formula (control group; n = 55); b) the same enteral formula enriched with arginine, RNA, and omega-3 fatty acids (enriched group; n = 55); and c) total parenteral nutrition (TPN group; n = 56). The three regimens were isocaloric and isonitrogenous. Enteral nutrition was started within 12 hrs following surgery. The infusion rate was progressively increased to reach the nutritional goal (25 kcal/kg/day) on postoperative day 4. MEASUREMENTS AND MAIN RESULTS: Tolerance of enteral feeding, rate and severity of postoperative complications, and length of hospital stay were recorded. Early enteral infusion was well tolerated. Side effects were recorded in 22.7% of the patients, but only 6.3% did not reach the nutritional goal. The enriched group had a lower severity of infection than the parenteral group (4.0 vs. 8.6; p < .05). In subgroups of malnourished (n = 78) and homologous transfused patients (n = 42), the administration of the enriched formula significantly reduced both severity of infection and length of stay compared with the parenteral group (p < .05). Moreover, in transfused patients, the rate of septic complications was 20.0% in the enriched group, 38.4% in the control group, and 42.8% in the TPN group. CONCLUSIONS: Early enteral feeding is a suitable alternative to TPN after major abdominal surgery. The use of the enriched diet appears to be more beneficial in malnourished and transfused patients.

Adult↗

PubMed1997

Effect of route of delivery and formulation of postoperative nutritional support in patients undergoing major operations for malignant neoplasms.

OBJECTIVE: To study the effect of the route of delivery and formulation of postoperative nutritional support on host defense, protein metabolism, infectious complications, and outcome. DESIGN: Prospective, randomized, clinical trial. SETTING: Department of Surgery at a university hospital. PATIENTS: Two hundred sixty candidates for pancreaticoduodenectomy or gastrectomy for cancer. INTERVENTIONS: Patients were randomly allocated into 3 groups during surgery. Starting 6 hours after operation, the first group received a standard enteral formula (standard group; n = 87); the second, the same enteral formula enriched with arginine, omega-3 fatty acids, and RNA (immunonutrition group; n = 87); and the third, total parenteral nutrition (parenteral group; n = 86). The 3 regimens were isocaloric and isonitrogenous. The nutritional goal was 105 kJ/kg per day. MAIN OUTCOME MEASURES: Immune response by phagocytosis ability of polymorphonuclear cells, interleukin (IL)-2 receptor levels, and delayed hypersensitivity response; protein synthesis by IL-6 and prealbumin; tolerance of enteral feeding; incidence of postoperative complications; and length of hospital stay. RESULTS: The immunonutrition group had a significantly better recovery of the immune parameters on postoperative day 8 compared with the other groups. Linear regression analysis showed an inverse correlation between IL-6 and preambulin levels (r = 0.766) only in the immunonutrition group. Only 11 patients (6.3%) in both enteral groups did not reach the nutritional goal. Postoperative infection rate was 14.9% (13/87) in the immunonutrition group, 22.9% (20/87) in the standard group, and 27.9% (24/86) in the parenteral group (P = .06). Mean +/- SD length of hospital stay was 16.1 +/- 6.2, 19.2 +/- 7.9, and 21.6 +/- 8.9 days in the immunonutrition, standard, and parenteral groups, respectively (P = .01 vs standard group; P = .004 vs parenteral group). CONCLUSIONS: Early postoperative enteral feeding is a valid alternative to parenteral feeding in patients undergoing major surgery. Immunonutrition enhances the host response, induces a switch from acute-phase to constitutive proteins, and improves outcome.

Aged↗

PubMed1997

Radical oncologic surgery affects the circulatory levels of interleukin 10.

BACKGROUND AND OBJECTIVE: Interleukin 10 (IL-10) has been shown to be elevated in the plasma of cancer-bearing patients. The source of systemic IL-10 may be the tumor microenvironment. We therefore tried to evaluate if ablative surgery for gastrointestinal cancer could affect the levels of circulating IL-10. METHODS: Plasma IL-10 concentration was measured in 45 patients with adenocarcinoma of the gastrointestinal tract. Forty healthy subjects, 15 women undergoing hysterectomy for uterine fibroma, and 15 patients undergoing palliative operation for pancreatic cancer were used as control groups. Plasma IL-10 was assessed 1 day before surgery (baseline) and 1, 4, and 8 days after operation. RESULTS: The baseline concentration of IL-10 was significantly higher in cancer patients than in healthy subjects and in women with fibroma (8.6 ng/mL, 2.1 and 1.8 respectively; P = 0.015). After radical surgery, the IL-10 levels significantly dropped in cancer patients (from 8.6 ng/mL to 3.8; P = 0.024), whereas in subjects undergoing palliative operation, the concentration remained elevated (8.5 ng/mL baseline versus 7.9 on day + 1). CONCLUSIONS: The origin of circulating IL-10 may be the tumor microenvironment.

Adenocarcinoma↗

PubMed1997

Effects of histaminergic antagonists on the GH-releasing activity of GHRH or hexarelin, a synthetic hexapeptide, in man.

The role of histamine in the neural control of GH secretion in man is still unclear, although a stimulatory influence has been hypothesized in man. To clarify this point, in 7 normal young women (23-28 yr) in their early follicular phase, we studied the effect of the histaminergic blockade by diphenhydramine (DPH, 80 mg os at -60 min) on the GH response to GHRH (2 micrograms/Hg iv) or Hexarelin (HEX, 2 micrograms/kg iv), a synthetic hexapeptide with strong GH-releasing effect. In 6 of the 7 women the effect of terfenadine (TRF, 120 mg os at -60 min), another H1-receptor antagonist, on the GH response to GHRH or HEX was also studied. As HEX has also PRL- and ACTH-releasing activity and histamine has been shown to have a stimulatory role in the neural control of these hormones, the effects of DPH or TRF on the HEX-induced PRL. ACTH and cortisol release were also studied. GHRH induced a GH rise (peak, mean +/- SEM: 35.4 +/- 6.5 vs 2.5 +/- 1.1 micrograms/l, p < 0.02, n = 7; 34.7 +/- 7.9 vs 3.9 +/- 1.5 micrograms/l, p < 0.02, n = 6) lower (p < 0.05) than that elicited by HEX (49.1 +/- 8.5 vs 3.9 +/- 1.0 micrograms/l, p < 0.01, n = 7; 48.7 +/- 8.9 vs 3.2 +/- 0.8 micrograms/l, p < 0.01, n = 6). DPH inhibited the GH response to both GHRH (AUC: 453.9 +/- 104.7 vs 1223.7 +/- 202.6 micrograms*min/l, p < 0.05) and HEX (922.0 +/- 215.4 vs 1636.4 +/- 267.5 micrograms*min/l, p < 0.05), although the HEX-induced GH rise persisted higher than that induced by GHRH (p < 0.05). TRF did not modify the GHRH-induced GH rise (950.5 +/- 369.2 mg*min/l vs 1115.3 +/- 255.6 micrograms*min/l) as well as the somatotrope responsiveness to HEX (1163.2 +/- 188.7 vs 1427.3 +/- 323.3 mg*min/l). HEX also significantly increased PRL (13.9 +/- 3.1 vs 6.5 +/- 0.8 micrograms/l, p < 0.03), ACTH (31.1 +/- 6.6 vs 16.6 +/- 2.9 pg/ml, p < 0.02) and cortisol (96.6 +/- 6.3 vs 82.2 +/- 6.2 micrograms/L, p < 0.05) levels. PRL, ACTH and cortisol responses to HEX were unaffected by DPH (536.5 +/- 85.6 vs 599.5 +/- 129.2 micrograms*min/l, 1068.5 +/- 306.0 vs 1282.8 +/- 222.0 pg*min/ml and 4277.4 +/- 588.4 vs 4738.3 +/- 355.3 micrograms*min/l, respectively) as well as by TRF (621.3 +/- 110.4 vs 530.3 +/- 131.4 micrograms*min/L, 972.4 +/- 189.6 vs 1060.2 +/- 224.7 pg*min/ml and 6203.8 +/- 1329.5 vs 5141.2 +/- 295.5 micrograms*min/l, respectively). In conclusion, our findings are against the hypothesis of a major role of H1-receptor-mediated histaminergic influence on GH secretion in humans. In fact, the H1-histaminergic blockade by TRF does not affect the GH response to GHRH or HEX; the inhibitory effect of DPH may probably be due to its intrinsic anticholinergic activity. Our data also confirm that Hexarelin releases more GH than GHRH and demonstrate that its effect on GH, PRL and ACTH release is not mediated by H1-receptors.

Administration, Oral↗

PubMed1997

Mechanisms underlying the negative growth hormone (GH) autofeedback on the GH-releasing effect of hexarelin in man.

The growth hormone (GH) response to GH-releasing hormone (GHRH) is strongly inhibited by previous administration of recombinant human GH (rhGH), likely as a consequence of a somatostatin-mediated GH negative autofeedback. Hexarelin (HEX), a synthetic hexapeptide belonging to the GH-releasing peptide (GHRP) family, possesses a GH-releasing activity greater than that of GHRH both in animals and in man. The mechanism of action of GHRPs is yet to be completely clarified, although concomitant actions at the pituitary and hypothalamic level have been hypothesized. To further clarify the mechanisms of action underlying the GH-releasing activity of HEX, in six normal young volunteers we studied the effects of rhGH (2 U intravenously [IV]) on the GH response either to GHRH (2 microg/kg IV) or to HEX (2 microg/kg IV) alone or combined with GHRH and/or pyridostigmine ([PD], 120 mg orally). The GH-releasing effect of HEX was higher than that of GHRH (area under the curve [AUC], 2,200.8 +/- 256.9 v 792.2 +/- 117.6 microg/L/h, P < .001), whereas combined administration of the two substances induced a true synergistic effect, with GH release after HEX plus GHRH (4,259.2 +/- 308.0 microg/L/h) being higher (P < .02) than the arithmetic sum of the GH increases induced by each compound separately administered. After rhGH administration, the GH-releasing effect of HEX was blunted (1,468.9 +/- 193.7 microg/L/h, P < .04; inhibition of 32.1%), whereas that of GHRH was nearly abolished (102.0 +/- 7.8 microg/L/h, P < .02; inhibition of 86.1%). The GH response to combined administration of HEX and GHRH was also blunted by the previous rhGH bolus (3,070.6 +/- 481.8 microg/L/h, P < .02; inhibition of 26.7%). PD did not modify the GH-releasing effect of HEX either alone (2,456.8 +/- 317.5 microg/L/h) or combined with GHRH (4,009.1 +/- 360.8 microg/L/h). rhGH was again able to blunt the GH response to HEX combined with PD (1,619.3 +/- 237.9 microg/L/h, P < .02), but failed to modify the GH response to HEX combined with GHRH and PD (4,548.4 +/- 698.0 microg/L/h). In conclusion, these results demonstrate that rhGH administration only blunts the GH-releasing activity of HEX, but abolishes that of GHRH. The blunting effect of rhGH on the GH response to HEX is probably mediated by a concomitant reduction in the activity of GHRH-secreting neurons and an increase of somatostatinergic tone.

Adult↗

PubMed1997

Low hexarelin dose and pyridostigmine have additive effect and potentiate to the same extent the GHRH-induced GH response in man.

OBJECTIVES: Hexarelin (HEX) is a synthetic hexapeptide belonging to the growth hormone-releasing peptide (GHRP) family. The exact mechanism underlying the strong GH-releasing activity of GHRPs is still unclear, though it has been shown that they act both at the pituitary and the hypothalamic level, where they have specific receptors. To clarify the influence of the cholinergic system on the GH-releasing activity of GHRPs in man, we investigated the effects of pyridostigmine, a cholinergic agonist which stimulates GH secretion by inhibiting somatostatin release, on the GH response to various HEX doses. DESIGN: We studied the GH release induced by various HEX doses (0.25, 0.5 and 2.0 micrograms/kg i.v.) and pyridostigmine (PD, 120 mg po), both alone and coadministered. The interactions between the lowest HEX dose or PD and the maximally effective GHRH dose (1.0 microgram/kg i.v.) were also studied. SUBJECTS: Six normal male volunteers, aged 24-30 years, were studied. MEASUREMENTS: Serum GH was measured in duplicate by immunoradiometric assay. RESULTS: The GH response to HEX administration was dose-dependent. In fact, the GH response to 0.25 microgram/kg HEX (AUC, mean +/- SEM: 816.4 (235.6 mU/l/120 min) was lower, although not significantly, than that to 0.5 microgram/kg HEX (2154.6 +/- 491.6 mU/l/120 min), which, in turn, was lower (p < 0.05) than that after 2.0 micrograms/kg HEX (4819.2 +/- 668.0 mU/l/120 min). The GH rise after GHRH (1299.2 +/- 222.8 mU/l/120 min) was lower (P < 0.05) than that after 2.0 micrograms/kg HEX, but not different from the responses to either 0.25 or 0.5 microgram/kg HEX. PD induced a significant GH rise (559.0 +/- 129.8 mU/l/120 min, P < 0.05 vs saline), similar to that after 0.25 microgram/kg HEX, and lower than those after both 0.5 and 2.0 micrograms/kg HEX (P < 0.05 and p < 0.01, respectively) and GHRH (p < 0.05). PD pretreatment enhanced the GH response to the lowest HEX dose (1961.4 +/- 253.8 mU/l/120 min, p < 0.05) in an additive way, but failed to modify the GH response to either 0.5 or 2.0 micrograms/kg HEX (2753.6 +/- 444.6 and 5179.0 +/- 770.8 mU/l/120 min, respectively). Notably, the GH response to 0.25 microgram/kg HEX + PD was still lower (P < 0.05) than that to 2.0 micrograms/kg HEX. PD pretreatment as well as 0.25 microgram/kg HEX truly potentiated the GH response to GHRH to the same extent (4926.6 +/- 912.8 mU/l/120 min, p < 0.05 and 5958.8 +/- 750.0 mU/l/120 min, p < 0.05 respectively). The GH responses to PD + GHRH and 0.25 microgram/kg HEX + GHRH were similar to that after 2.0 micrograms/kg HEX alone. CONCLUSIONS: Our results demonstrate that pyridostigmine is able to enhance the GH response only to a very low dose Hexarelin which, in turn, potentiates the GHRH-induced GH rise to the same extent as pyridostigmine. As there is evidence that GHRPs do not inhibit hypothalamic somatostatin release, these findings are consistent with the hypothesis that they act by antagonizing somatostatin activity and/or through unknown factors. On the other hand, though there is evidence showing that GHRH activity is needed for GHRP action, our findings indicate that GHRPs act, at least partially, independently of GHRH.

Adult↗

PubMed1997

Adrenocorticotropin- and cortisol-releasing effect of hexarelin, a synthetic growth hormone-releasing peptide, in normal subjects and patients with Cushing's syndrome.

GH-releasing peptides (GHRPs) are synthetic, nonnatural molecules that strongly stimulate GH secretion, but also slightly increase PRL, ACTH, and cortisol levels in man. To investigate the mechanism underlying the ACTH- and cortisol-releasing activity of GHRPs in man, we compared the ACTH- and cortisol-releasing activity of Hexarelin (HEX; 2.0 micrograms/kg, iv), a hexapeptide belonging to the GHRP family, with that of human CRH (hCRH; 2.0 micrograms/kg, iv) in normal subjects (6 men and 6 women, 24-68 yr old) and patients with Cushing's syndrome (2 men and 15 women, 16-68 yr old). The GH response to HEX administration was also studied. In normal subjects, HEX administration significantly increased ACTH (peak us. baseline, mean +/- SD, 32.4 +/- 17.7 vs. 16.3 +/- 7.2 pg/mL; P < 0.005) and cortisol levels (135.9 +/- 51.0 vs. 110.0 +/- 31.6 micrograms/L; P < 0.01). The ACTH and cortisol responses to hCRH [35.7 +/- 13.2 vs. 17.1 +/- 7.7 pg/mL (P < 0.01) and 162.8 +/- 50.1 vs. 102.8 +/- 28.1 micrograms/L (P < 0.01), respectively] were similar to the responses to HEX. The stimulatory effect of HEX, but not that of hCRH, on both ACTH and cortisol secretion in Cushing's disease was clearly higher (P < 0.01) than that observed in normal subjects. In fact, in Cushing's disease both HEX and hCRH elicited a clear increase in ACTH levels [381.1 +/- 350.0 vs. 52.4 +/- 25.0 (P < 0.005) and 100.0 +/- 86.2 vs. 53.3 +/- 29.7 pg/mL (P < 0.01), respectively but the ACTH increase induced by HEX was about 7-fold greater (P < 0.02) than that induced by hCRH. Similarly, both HEX and hCRH elicited a significant increase in cortisol levels [366.9 +/- 189.5 vs. 189.7 +/- 86.3 micrograms/L (P < 0.005) and 209.9 +/- 125.4 vs. 167.2 +/- 96.3 micrograms/L (P < 0.02), respectively], but the cortisol increase induced by HEX was about 4-fold greater (P < 0.05) than that induced by hCRH. In patients with Cushing's syndrome due to adrenal adenoma or ectopic ACTH, no change in ACTH and cortisol levels was observed after either HEX or hCRH administration. The peak GH response to HEX in normal subjects was clearly higher (P < 0.03) than that in hypercortisolemic patients (45.8 +/- 20.5 vs. 22.4 +/- 21.1 micrograms/L). In conclusion, the ACTH- and cortisol-releasing activity of HEX is similar to that of hCRH in normal subjects, whereas it is dramatically enhanced in patients with Cushing's disease. This evidence indicates the importance of the ACTH-releasing activity of GHRPs and suggests that it could be at least partially independent of CRH-mediated mechanisms. As the stimulatory effect of HEX on ACTH and cortisol secretion is lost in patients with Cushing's syndrome due to adrenal adenoma or ectopic ACTH, these findings suggest the usefulness of GHRPs to investigate the activity of the hypothalamo-pituitary-adrenal axis in pathophysiological conditions and possibly to differentiate pituitary from ectopic ACTH-dependent Cushing's syndrome.

Adolescent↗

PubMed1997

Oestrogen replacement does not restore the reduced GH-releasing activity of Hexarelin, a synthetic hexapeptide, in post-menopausal women.

Hexarelin (HEX), a synthetic hexapeptide, has a strong and reproducible GH-releasing activity in man after intravenous, subcutaneous, intranasal and oral administration. Its effect undergoes age-related variations, being reduced in elderly subjects. In spite of evidence in animals showing that the activity of GH-releasing peptides (GHRPs) is positively influenced by oestrogens, in young adults no sex-related difference has been found in the GH response to HEX or to other GHRPs. We aimed to clarify the influence of the menopause and oestrogens on the GH-releasing activity of HEX. We studied the GH response to the acute administration of the maximal effective dose of HEX (2 micrograms/kg i.v.) in 24 young women (YW, age: 27.3 +/- 0.5 years: body mass index (BMI): 20.7 +/- 0.3 kg/m2), 14 post-menopausal women (PW, age: 52.9 +/- 1.2 years: BMI: 23.2 +/- 0.9 kg/m2) and 14 aged women (AW, age: 68.9 +/- 1.5 years: BMI: 21.7 +/- 0.7 kg/m2). In 10 post-menopausal women the GH response to HEX was also studied after 3 months of transdermal oestradiol treatment (delivery 50 micrograms/die). Basal oestrogen and GH levels in PW were lower than those in YW (oestrogen: 4.8 +/- 3.6 vs 42.0 +/- 3.4 pg/ml (means +/- S.E.M.). P < 0.001: GH: 1.5 +/- 0.5 vs 2.9 +/- 0.6 micrograms/l, P < 0.02) and similar to those in AW (oestrogen: 1.3 +/- 0.4 pg/ml: GH: 0.9 +/- 0.2 microgram/l). IGF-l levels in PW were not different from those in YW (174.4 +/- 11.9 vs 195.5 +/- 14.9 micrograms/l) and higher than those in AW (109.8 +/- 15.8 micrograms/l, P < 0.01). The GH response to HEX in PW (areas under the curve +/- S.E.M.: 453.6 +/- 56.0 micrograms.min/l) was lower (P < 0.002) than that in YW (1630.4 +/- 259.7 micrograms.min/l) while it did not differ from that in AW (781.8 +/- 189.3 micrograms.min/l). In PW 3-month oestrogen administration increased oestradiol levels (38.3 +/- 5.9 vs 0.8 +/- 0.4 pg/ml, P < 0.001) making them similar to those recorded in YW, while it failed to modify both basal GH and IGF-l levels GH: 1.8 +/- 0.6 vs 1.5 +/- 0.7 micrograms/l: IGF-l: 164.6 +/- 14.3 vs 175.0 +/- 12.3 micrograms/l). Also the GH response to HEX was not modified by oestradiol treatment (518.4 +/- 125.6 vs 425.4 +/- 69.3 micrograms.min/l). In conclusion, present data confirm the strong GH-releasing effect of Hexarelin in humans and demonstrate that its activity is already reduced in post-menopausal women to an extent overlapping that in elderly women. Moreover, oestrogen treatment is not able to restore it. Thus, the lack of oestrogens does not seem to account for the reduced somatotraph responsiveness to GHRPs in the post-menopausal period.

Adult↗

PubMed1996

Increased interleukin-10 serum levels in patients with solid tumours.

In 40 out of 99 patients (40.4%) with solid tumours of different tissue, but the same stage (IV), elevated serum levels of interleukin-10 were observed. The mean levels of the cytokine in patients with malignant melanoma (24.3 ng/ml), pancreatic (6.8 ng/ml) or gastric (6.3 ng/ml) adenocarcinoma were significantly higher than in healthy subjects (3.4 ng/ml) or in patients with uterine fibroma (1.7 ng/ml). Patients with colon (6.8 ng/ml) and renal (5.7 ng/ml) carcinoma had similar values of interleukin-10 but did not significantly differ from controls. Interleukin-10 is known to suppress the functions of both T lymphocytes and macrophages, working as a general dampener of the immune and inflammatory responses. The observation of increased circulating levels of interleukin-10 in cancer patients may have important implications for future investigations, immunological monitoring and therapeutic intervention on neoplastic patients, and suggests a mechanism for tumour cells escaping from immune surveillance.

Adult↗

PubMed1996

Gut function and immune and inflammatory responses in patients perioperatively fed with supplemented enteral formulas.

OBJECTIVE: To evaluate if the perioperative administration of a supplemented enteral formula modulates selective inflammatory and immune variables and gut function after surgery. DESIGN: Prospective, randomized, double-blind, clinical trial. SETTING: Department of surgery, university hospital. PATIENTS: Forty patients with neoplasm of the colorectum or stomach. INTERVENTION: Seven days before surgery, the patients drank 1 L/d of a control enteral formula (n = 20) or the same formula enriched with arginine, RNA, and omega-3 fatty acids (n = 20). Jejunal infusion with the same formulas was started 6 hours after operation and continued until day 7. MAIN OUTCOME MEASURES: Immune response was determined by phagocytosis ability and respiratory burst of polymorphonuclear cells, and inflammatory response by plasma levels of C-reactive protein. Operative intestinal microperfusion, postoperative intestinal mucosa oxygen metabolism, and plasma intestinal isoenzyme of alkaline phosphatase were used as indicators of gut function. Plasma nitric oxide also was determined. RESULTS: In the enriched group, phagocytosis ability and respiratory burst after surgery was higher (P < .01) and C-reactive protein level was lower (P < .05) than in the control group. The enriched group had higher mean (+/-SD) intestinal microperfusion (180 +/- 46 vs 146 +/- 59 perfusion units, P < .05), intestinal mucosa oxygen metabolism (pHi 7.39 +/- 0.2 vs pHi 7.33 +/- 0.1, P < .05), and 5-fold lower levels of intestinal isoenzyme of alkaline phosphatase (P < .05). Postoperative levels of nitric oxide were higher in the enriched group (P < .05, analysis of variance). CONCLUSION: The perioperative administration of an enriched enteral formula significantly improved gut function and positively modulated postsurgical immunosuppressive and inflammatory responses.

Adolescent↗

PubMed1996

Steroid therapy can modulate gut barrier function, host defense, and survival in thermally injured mice.

Prednisone may be immunosuppressive and dehydroepiandrosterone may stimulate the immune response, but their effect on gut-origin sepsis caused by bacterial translocation has not been studied. Balb/c mice were treated orally with prednisone (1 or 10 mg/kg/day) or saline for 4 days before receiving gavage with 10 (10) 14 C-labeled Escherichia coli and a 20% thermal injury. Mice were transfused with allogeneic blood and given dehydroepiandrosterone (5 or 25 mg/kg/day) or vehicle subcutaneously for 4 days before bacterial gavage and thermal injury. Some groups in each experiment were observed 10 days for mortality and others were sacrificed 4 hr postburn to measure translocation and survival of translocated bacteria. Survival in prednisone treated animals was 25% (10 mg/kg/day) and 75% (1 mg/kg/day) versus 80% for controls. Following dehydroepiandrosterone administration, survival was 72% (25 mg/kg/day/group) and 30% (5 mg/kg/day/group) versus 16% for controls. High dose prednisone increased bacterial translocation to the intestinal wall and mesenteric lymph nodes and greatly impaired killing of translocated E. coli. In contrast, dehydroepiandrosterone (25 mg/kg) did not affect translocation but significantly improved bacterial killing. Prednisone and dehydroepiandrosterone exert opposite effects during gut-derived sepsis.

Animals↗

PubMed1996

Thymopentin modulates Th1 and Th2 cytokine response and host survival in experimental injury.

OBJECTIVE: To investigate the impact of thymopentin (Thy) on mortality and in vivo cytokine release in an animal model of gut-derived sepsis which includes different combinations of allogeneic blood transfusion (T) and burn injury plus bacterial gavage (BG). DESIGN: Randomly controlled experiments. MATERIAL: Two hundred sixteen Balb/c (H-2d) and 50 C3H/HeJ (H-2k) mice. INTERVENTIONS: In the first study 60 Balb/c mice were given Thy (1 mg/kg). The same day of therapy onset, 40 mice were transfused with allogeneic blood (from C3H/HeJ mice). The remaining 20 mice received aliquots of saline. Five days post-T, 20 of the 40 transfused mice were subjected to a 20% TBSA thermal injury and simultaneous gavage with 1 x 10(9) Escherichia coli and the other 20 mice underwent a sham burn. The 20 nontransfused mice also received a 20% burn plus bacterial gavage. In all animals Thy was administered for 15 days. Three control groups (n = 20 each) entered the same protocol design, but they did not receive Thy. In the second study 96 animals were randomized to six groups (n = 16 each) according to the above experimental design. Animals were sacrificed by exsanguination after burn or 5 days post-T in nonburned mice to measure TNF-alpha, IL-2, and IL-4 plasma levels. RESULTS: The highest mortality (70%) occurred when T was combined with BG. Thy significantly reduced mortality in both groups that underwent BG, regardless of the association with T. TNF-alpha was detectable in 30% of the tested samples, IL-2 in 50%, and IL-4 in 70%. Thy significantly reduced the levels of IL-4 and increased the production of IL-2. CONCLUSIONS: The protective effect of Thy in this experimental model may be mediated by modulation of cytokine release.

Adjuvants, Immunologic↗

PubMed1996

Influence of beta-adrenergic agonists and antagonists on the GH-releasing effect of Hexarelin in man.

Beta-adrenergic receptors mediate the inhibitory influence of cathecolamines on GH secretion, probably via the stimulation of hypothalamic somatostatin release. Accordingly, beta-adrenergic agonists and antagonists inhibit and increase, respectively, the GH response to many stimuli, including GHRH, in man. Aim of the present study was to verify the effect, if any, of beta-adrenergic drugs on the GH response to Hexarelin, a synthetic GH-releasing hexapeptide. Interestingly, the GH-releasing effect of Hexarelin has been reported to be partially refractory to neuroendocrine manipulations known to strongly enhance or abolish the GHRH-induced GH release. In 6 normal male volunteers (aged 22-27 yr) we studied the interaction of the maximally effective iv dose of Hexarelin (HEX, 2 micrograms/kg iv at 0 min) with atenolol (100 mg po at -60 min) or salbutamol (0.08 mg/kg po at -60 min), which are beta-adrenergic antagonist and agonist, respectively. HEX induced a marked GH rise (AUC, mean +/- SE: 4573.2 +/- 588.8 micrograms.min/L), which was unchanged by atenolol (4706.2 +/- 928.2 micrograms.min/L) but blunted by salbutamol (2792.8 +/- 618.0 micrograms.min/L, p < 0.03). In conclusion, present data show that, in man, the GH-releasing effect of Hexarelin is not enhanced by beta-adrenergic blockade while is only blunted by the activation of beta receptors. According to other data, these results indicate that the potent GH-releasing activity of Hexarelin is, at least partially, refractory to beta-adrenergic-mediated manipulations of somatostatinergic activity.

Adrenergic beta-Agonists↗

PubMed1996

Galanin positively modulates prolactin secretion in normal women.

It is widely accepted that, in man, galanin, a neuropeptide, has a clear GH-releasing effect while its stimulatory influence on PRL secretion is matter of debate. To clarify this point, in 6 normal young women (23-35 yr) in their early follicular phase, we studied the effect of galanin (pGAL, 80 pmol/kg. min infused i.v. over 60 min) on both basal and arginine (ARG, 0.5 g/kg i.v. in 30 min), TRH (400 micrograms i.v. as a bolus at 0 min) or metoclopramide (MCP, 10 mg i.v. as a bolus at 0 min)-stimulated PRL secretion. GAL infusion failed to significantly increase basal PRL levels (peak vs baseline: 12.2 +/- 3.6 vs 8.7 +/- 1.2 micrograms/L) but counteracted the spontaneous PRL decrease observed during saline infusion (AUC: 1216.6 +/- 282.1 vs 672.0 +/- 94.5 micrograms.min/L; p < 0.05). GAL infusion clearly enhanced the PRL response to TRH (AUC: 5806.3 +/- 743.0 vs 3952.1 +/- 423.9 micrograms.min/L, p < 0.05) and ARG (AUC: 3676.8 +/- 382.6 vs 2638.9 +/- 287.0 micrograms.min/L, p < 0.05), respectively. On the other hand, GAL failed to modify the MCP-induced PRL response (AUC: 15409.5 +/- 2085.3 vs 14,787.9 +/- 2045.5 micrograms.min/L). The PRL response to MCP was higher than that to TRH (p < 0.01) which, in turn, was higher than that to ARG (p < 0.01). During GAL infusion, the PRL response to TRH or ARG remained lower (p < 0.01) than that after MCP administration. Thus, in conclusion, present data demonstrate that in normal women galanin enhances the PRL response to ARG and TRH but fails to modify that induced by dopamine receptor blockade with metoclopramide. Based on evidence that the inhibition of central dopaminergic activity inhibits the lactotrope responsiveness to dopaminergic antagonists or TRH, it is unlikely that galanin influences PRL secretion via inhibition of dopaminergic tone.

Adult↗

PubMed1996

Nutritional support to prevent and treat multiple organ failure.

Enteral nutrition (EN) has several advantages over parenteral nutrition (PN) for postoperative/posttrauma patients. Modern technologies for tube-feeding have made early EN possible. Jejunal tube-feeding has advantages over gastric tube-feeding: faster metabolic recovery, less vomiting, and less risk of regurgitation and aspiration. Immediate or early EN stimulates the splanchnic and hepatic circulations, improves mucosal blood flow, prevents intramucosal acidosis and permeability disturbances, and eliminates the need for stress ulcer prophylaxis. Saliva containing important antimicrobial substances and gastric acidity are important in sepsis prevention. Chewing, saliva, and gastric acidity support gastric nitric oxide (NO) release, important for mucosal blood flow, gastrointestinal (GI) motility, mucus formation, and bacteriostasis. An oral supply of NO-donating substances and chewing of nitrate-rich food, such as lettuce or spinach, can be useful. Oral and mucosa-protective lipids are recommended. H2 blockers and saliva-inhibiting drugs are avoided. Immediate EN should be given, starting with 25 ml/hr and increasing to 100 ml/hr over 24 to 48 hours. For the immunocompromised patient special attention should be given to the purity of water. Bottled water can contain bacteria such as Pseudomonas. Food antioxidants such as glutathione, vitamin E, and beta-carotenes are important. Ingredients for the colonic mucosa are important. Approximately 10% of caloric need is satisfied by so-called colonic food (prebiotics), fermented at the level of the colonic mucosa to produce colonic mucosa nutrients and to prevent gut origin sepsis. More than 10 g of fiber per day is recommended. The fermenting flora (probiotic flora) is deranged owing to disease or antibiotic treatment, and resupply of flora is important. A new concept of ecoimmune nutrition is presented for enteral supply of mucosa-reconditioning ingredients: new surfactants, pseudomucus, fiber, amino acids such as arginine, and mucosa-adhering Lactobacillus plantarum 299.

Energy Intake↗

PubMed1996

Experimental gut-derived endotoxaemia and bacteraemia are reduced by systemic administration of monoclonal anti-LPS antibodies.

This study aimed to investigate the effects and mechanisms of action of systemic administration of monoclonal antibodies, anti-endotoxin (HA-1A), in an animal model of gut-origin sepsis. In the first experiment, Balb/c mice were transfused with allogeneic blood (C3H/HeJ mice). Five days post-transfusion the animals were gavaged with 1 x 10(9) Escherichia coli and randomized into three groups (n = 22 each) to receive a sham burn (SB group) or a 20 per cent TBSA thermal injury, immediately followed by the systemic administration of monoclonal antibodies (3 mg/kg) (HA-1A group) or aliquots of sterile saline (Control group). The animal survival rate was observed for 10 days postburn. In the second experiment transfusion and burn injury were reproduced but the mice (n = 8/group) were gavaged with 10(9) E.coli labelled with 111indium oxine. Four hours after the burn the mesenteric lymph nodes, liver, lungs and blood were harvested to determine plasma endotoxin levels and the magnitude of translocation of labelled bacteria measured by the residual radioactivity in the organs. Circulating endotoxin levels were determined by limulus assay. The mortality rate of the HA-1A group (9 per cent) was similar to the SB group (0 per cent) and significantly lower than the control group (59 per cent) (P < 0.05). Both plasma endotoxin levels and degree of bacterial translocation in all extraintestinal tissues were significantly lower (by approximately 50 per cent) in the HA-1A group than in the control group (P < 0.05). Systemic administration of HA-1A exerts a beneficial effect by reducing the circulating levels of endotoxin and by increasing the gut barrier function to translocating microorganisms.

Analysis of Variance↗

PubMed1996

High protein diets are associated with increased bacterial translocation in septic guinea pigs.

During sepsis, body protein stores are decreased due to an increase in protein catabolism. The utilization of nutritional support with high-protein diets has been used as a solution to the problem of sepsis-induced protein loss. Work from our laboratory, however, has shown that diets low in protein (5% of total calories) improve survival in septic animals as compared to high protein (20%) diets. The present study investigated the relationship between low-protein diets and improved survival by determining whether septic animals receiving high-protein diets have increased bacterial translocation. Sepsis was induced in guinea pigs by the implantation of an osmotic minipump into the peritoneal cavity containing an equal mixture of Escherichia coli (10(8)) and Staphylococcus aureus (10(8)) or saline. On Day 3 postlaparotomy, the animals were randomized to one of four groups. The groups consisted of septic and nonseptic animals that received a diet with 5 or 20% of total calories as protein. Following 4 days of diet all animals received an instillation of 14C labeled E. coli (10(10)). Four hours later the animals were sacrificed and blood, mesenteric lymph nodes, spleen, lungs, and liver were removed for determination of radionuclide counts. Results indicated that the septic animals that received the high protein diet had more bacterial translocation, as indexed by higher radionuclide counts in the MLN, liver, lung and blood. These findings suggest that a low protein, enterally fed diet may improve survival in septic patients by decreasing the incidence of bacterial translocation.

Animals↗