Biomedical subjects

E E Müller

Publications and source records attributed to E E Müller.

At least 19 recordsLinked to original sources

PubMed2006

The leukocyte expression of CD36 is low in patients with Alzheimer's disease and mild cognitive impairment.

CD36, a scavenger receptor of class B (SR-B), helps mediate microglial and macrophage response to beta-amyloid fibrils (betaA), and seems to play a key role in the proinflammatory events associated with Alzheimer disease (AD) in many tissues. Peripheral leukocytes express many molecules and multiple receptors which undergo the same regulatory mechanisms as those operative in the brain. Thus, these cells, easily obtainable through peripheral blood sampling, may be used as a tool to investigate changes occurring in inaccessible brain areas. Based on these premises, we investigated the leukocyte expression of CD36 in 70 AD patients and in 30 subjects with mild cognitive impairment (MCI). Results were compared to those of 20 young and 40 age-matched control subjects. Leukocyte expression of CD36 was significantly reduced versus controls in both AD and MCI patients, while in young and old controls there were no age-related changes. Although preliminary, these data indicate that the reduction of CD36 expression in leukocytes is a disease-related phenomenon, occurring since the early stages of AD (MCI). Irrespective of the mechanism(s) underlying such changes, assessment of leukocyte CD36 expression might represent an useful tool to support the diagnosis of AD and to screen MCI patients candidates to develop the disease.

Adult↗

PubMed2006

A follow-up of GH-dependent biomarkers during a 6-month period of the sporting season of male and female athletes.

In order to verify the effects of the sporting season (entailing periods of training, competition, recovery, resting) on GH-dependent parameters in male and female athletes from different sporting disciplines, 47 male and female athletes (3 rowers, 5 swimmers, 7 alpine skiers, 3 soccer players, 7 middle distance runners, 14 sprinters, 4 triathletes, 1 road walker, 3 cyclists) were followed-up for a period of 6 months. Blood samples were taken every two months for the evaluation of IGF-I, N-terminal propeptide of type III procollagen (PIIINP) and C-terminal cross-linked telopeptide of type I collagen (ICTP). Abnormal IGF-I, PIIINP and ICTP levels were observed during the follow-up period in 7/100 (7%), 9/100 (9.0%) and 8/100 (8%) samples of the male group, respectively, and in 9/88 (10.2%), 1/88 (1.1%) and 0/88 (0%) samples of the female group, respectively. Abnormal levels appeared to be randomly distributed over the different periods of the sporting season and within male and female subjects, with the large majority of abnormal values being found in the younger athletes. Taking into account all the tests done during the 6-month period (no. 564), individual markers falling outside the normal range (for age) were observed in a small number of instances (34/564 tests done, 24/300 for males and 10/264 for females). When our method for the detection of exogenous recombinant GH (rhGH) administration, based on the concomitant determination of these three peripheral GH-dependent markers and on the attribution of specific scores, was applied in the same athlete at a given time point of the 6-month period, the prevalence of a positive score was extremely low (ie, 3/188 samples or 1.6%). Total positive scores were actually recorded in only three male athletes (2 swimmers and 1 skier, aged <21 yr) at one occasion during the 6-month period considered. In contrast, no total positive scores were found in female athletes (ie, 0/88 samples). In conclusion, the concentrations of IGF-I, PIIINP and ICTP were stable and not significantly modified during 6 months of a sporting season (entailing periods of training, competition, recovery, resting) in athletes from different sporting disciplines. Therefore our method, based on the concomitant determination of three peripheral GH-dependent biomarkers appears safe, acceptable, relatively inexpensive and repeatable (in case of positive or suspected values) immediately or at different intervals of the sporting season. Further additional studies are requested to precise the cut-off values for narrower age-class subdivisions in both genders in order to improve the proposed method.

Adolescent↗

PubMed2004

Gender-, age-, body composition- and training workload-dependent differences of GH response to a discipline-specific training session in elite athletes: a study on the field.

Ninety-nine Italian elite athletes (61 M, 38 F, mean age +/- SE: 24.1 +/- 0.6 yr, age range: 17-47 yr) of different disciplines volunteered to participate in this investigation. Basal GH concentrations were significantly higher (p<0.0001) in females (6.2 +/- 1.1 ng/ml) vs males (1.9 +/- 0.5 ng/ml). Basal GH values were negatively correlated with age and body mass index (BMI); no significant correlation was found between GH and IGF-I levels. Among female athletes, 8/38 had basal GH values higher than 10 ng/ml [2/8 athletes were taking oral contraceptives (OC)], while among males 6/61 had values higher than 5 ng/ml. In females, training sessions significantly increased (p<0.0001) basal GH concentrations (peak GH: 18.5 +/- 1.9 ng/ml), while in males GH responses were lower than in females (11.8 +/- 1.4 ng/ml, vs F: p<0.005). Six out of 38 female and 6/61 male athletes were considered GH hypo-responders (i.e. negative difference between peak GH and basal GH values), the large majority of them being subjects with elevated basal GH concentrations. In responsive athletes, peak GH values occurred immediately at the end of the training session both in males and in females; GH concentrations rapidly declined during recovery. No significant correlations were found between peak GH and age, body weight and BMI in either gender. GH responses were directly related (p<0.001) to the intensity of the workload during the sessions. In conclusion, the present study demonstrates that: 1) some elite athletes had increased GH concentrations before training, which were however associated with normal IGF-I levels; 2) GH peaks after a discipline-specific training session were significantly higher in females than in males performing the same discipline, gender-related differences disappearing when post-exercise total GH outputs (area under the curve) were compared; 3) peak GH values were directly correlated with training workload; 4) GH concentrations rapidly declined during recovery, values at the end of the post-training GH sampling being generally lower than those found in basal condition.

Adolescent↗

PubMed2004

IGF-I stimulates proliferation of spontaneously immortalized human keratinocytes (HACAT) by autocrine/paracrine mechanisms.

HaCaT keratinocytes are derived from adult human skin and although spontaneously immortalized, remain highly related to their normal counterparts. We observed that HaCaT cells can proliferate in serum-free medium (SFM), in contrast to normal human keratinocytes whose growth in vitro requires a feeder layer and/or the supplementation with hormones and growth factors. Since autocrine production of growth factors has been proposed as the pathway that cells may exploit to escape growth regulation, we have investigated whether this is occurring in HaCaT cultured in SFM. Either epidermal growth factor (EGF) or insulin-like growth factor-1 (IGF-I) was effective and dose-dependently stimulated HaCaT replication. The ability of these keratinocytes to express EGF and IGF-I and their receptors was investigated by northern blot and reverse transcriptase-polymerase chain reaction (RT-PCR). We report that HaCaT cells synthesize mRNAs for IGF-I, IGF-II, IGF-IR and EGF-R but not EGF mRNA. Immunoneutralization of IGF-I with specific monoclonal antibodies blocked spontaneous HaCaT proliferation in SFM, as did incubation with antibodies against IGF-IR. These data demonstrate that an autocrine/paracrine loop based on IGF-I may allow HaCaT keratinocytes to proliferate autonomously in culture in contrast to keratinocytes in primary culture. A similar mechanism may be involved in the development of hyperproliferative diseases of human skin and its functional disruption may represent the target for therapeutic approaches.

Adult↗

PubMed2004

Maintenance of a normal meal-induced decrease in plasma ghrelin levels in children with Prader-Willi syndrome.

Ghrelin is a 28-amino acid peptide recently identified in the stomach as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R1a). Ghrelin is a potent stimulator of GH secretion. It was recently shown that circulating ghrelin levels in humans rise shortly before and fall shortly after every meal, and that ghrelin administration increases voluntary food intake. The hypothesis that ghrelin hypersecretion might contribute to genetic obesity has never been investigated. In this context, Prader-Willi syndrome is the most common form of human syndromic obesity. As ghrelin affects appetite as well as GH secretion and both are abnormal in PWS, it has been surmised that these alterations might be due to ghrelin dysregulation. The aim of the study was to investigate whether ghrelin is suppressed by the meals differently in PWS children than in PWS adults. Overnight circulating fasting ghrelin levels and ghrelin levels 120 min after breakfast were assayed in 7 PWS children (10.2 +/- 1.7 yr), 7 subjects with morbid obesity (10.3 +/- 1.3 yr), and 5 normal controls (8.4 +/- 1.4 yr). Because of the data spread, no statistical difference was observed in fasting ghrelin levels between PWS and control children (p = NS); anyway, fasting ghrelin levels were significantly lower in obese children than in the other groups (p < 0.05 vs. control and PWS children). Ghrelin levels were slightly suppressed by the meal in control subjects (mean fasting ghrelin: 160.2 +/- 82 pg/ml; after the meal, 141.2 +/- 57 pg/ml, p = NS); the meal failed to suppress ghrelin levels in obese children (mean fasting ghrelin: 126.4 +/- 8.5 pg/ml; after the meal, 119.1 +/- 8.3 pg/ml, p = NS). Interestingly, the meal markedly suppressed ghrelin levels in PWS children (mean fasting ghrelin: 229.5 +/- 70.4 pg/ml; after the meal, 155.8 +/- 34.2 pg/ml, p < 0.01). In conclusion, since a lack of decrease in circulating ghrelin induced by the meal was previously reported in PWS adults, the finding of a meal-induced decrease in ghrelin levels in our population of young PWS would imply that the regulation of the ghrelin system involved in the orexigenic effects of the peptide is operative during childhood, although it progressively deteriorates and is absent in adulthood when hyperphagia and obesity progressively worsen.

Adipose Tissue↗

PubMed2003

[Delirium increases morbidity and length of stay after vascular surgery operations. Results of a prospective study].

OBJECTIVE: We intended to analyze the influence of postoperative delirium on postoperative morbidity and length of hospital stay. PATIENTS AND METHOD: 153 patients undergoing elective arterial surgery were studied prospectively. Patients were examined postoperatively by a psychiatrist daily from days 1 to 7. Delirium was diagnosed according to standardised criteria (Diagnostic and Statistical Manual of Mental Disorders). The severity of delirium was quantified using the Delirium Rating Scale. We compared patients without delirium to those who developed postoperative delirium using univariate statistical analysis (t-test, chi (2) test, and Fisher's test). RESULTS: Sixty patients (39.2%) developed postoperative delirium. They removed catheters significantly more frequently than patients without delirium and had more catheter-related infections. Their length of stay in intensive care units was higher, as was their total postoperative length of stay in hospital. CONCLUSIONS: Patients who developed postoperative delirium have significantly more complications and increased postoperative length of stay in hospital and intensive care units.

Aged↗

PubMed2003

Mechanisms of action of GH.

The process of growth, which is common to all multicellular organisms, is complex and involves the interaction of a multiplicity of factors; despite this, the GH/IGF function still maintains its preminence, and, in turn, the same is true for all approaches aimed at reducing the consequences of GH/IGF excess. In this review paper, we will deal briefly with some aspects of GH/IGF mechanism of action which are instrumental to the appreciation of a novel class of a "designer" GH antagonist, for use in conditions characterized by excess GH action and elevated serum IGF-I.

Animals↗

PubMed2002

GH and cortisol rebound rise during and following a somatostatin infusion: studies in dogs with the use of a GH-releasing peptide.

GH-releasing peptides (GHRPs), a class of small synthetic peptide and non-peptide compounds, act on specific receptors at both the pituitary and the hypothalamic level to stimulate GH release in both humans and other animals. GHRPs, like corticotropin-releasing hormone (CRH), also possess acute ACTH- and cortisol-releasing activity, although the mechanisms underlying the stimulatory effect of GHRPs on the hypothalamo-pituitary-adrenal (HPA) axis are still unclear. In recent years, studies in humans and other animals have provided evidence that the rebound GH rise which follows withdrawal of an infusion of somatostatin (SS) (SSIW) is due, at least in part, to the functional activation of GH-releasing hormone (GHRH) neurons of the recipient organism. Unexpectedly, in humans, SS infusion, at a dose inhibiting basal GH secretion, has been associated with an activation of the HPA axis, leading to the hypothesis that this response was mediated, at least in part, by a central nervous system ACTH-releasing mechanism activated by the SS-induced decrease in GH secretion. Interestingly, the rebound GH rise which follows SSIW was magnified by the administration, before SS withdrawal, of a GHRP, implying that the SSIW approach could also be exploited to investigate in vivo the functional interaction in the process of GH and/or ACTH/cortisol secretion between endogenous GHRH (and/or other ACTH-releasing mechanisms) and GHRPs. In the present study, six young beagle dogs were given, on different occasions, at the beginning and at the end of a 3-h i.v. infusion of SS or saline (SAL), a bolus of physiological SAL or a GHRP compound, EP51216. SSIW induced a GH rebound rise without affecting plasma cortisol concentrations, while the withdrawal of SAL infusion was ineffective on either hormone paradigm. Administration of EP51216 at the beginning of SAL infusion evoked release of both GH and cortisol, whereas EP51216 administration at the withdrawal of SAL infusion evoked somatotroph and cortisol responses which were reduced in amplitude and duration. SS infusion significantly reduced the secretion of GH elicited by EP51216 but did not affect the rise of plasma cortisol levels. Interestingly, SSIW resulted in a marked enhancement of the somatotroph and cortisol responses evoked by EP51216. The marked rise of plasma GH levels induced by the GHRP after SSIW recalled that occurring after acute combined administration of recombinant human GHRH and EP51216, implying that exogenously delivered GHRP had synergized with the endogenous GHRH release triggered by SSIW. In contrast, acute combined administration of GHRH and the GHRP induced a cortisol response not different from that induced by GHRP alone, indicating that endogenous GHRH release was not involved in the enhanced cortisol response following EP51216 administration after SSIW. Similarly, the direct involvement of endogenous CRH could be ruled out, since i.v. administration of ovine CRH after SSIW evoked cortisol peak levels not different from those evoked by CRH at the withdrawal of SAL infusion. In conclusion, enhancement of the GH response to EP51216 alone by SSIW, to an extent reminiscent of that following combined administration of GHRH and EP61216, reinforces the view that SSIW elicits release of endogenous GHRH. Further studies are indeed necessary for a better understanding of the mechanisms underlying the enhanced cortisol response, since from now on the involvement of endogenous GHRH or CRH can be ruled out.

Analysis of Variance↗

PubMed2002

Plasma ghrelin concentrations in elderly subjects: comparison with anorexic and obese patients.

Ghrelin, a novel endogenous ligand for the GH secretagogue receptor, has been reported to stimulate GH secretion and food intake in both humans and other animals. Interestingly, recent data indicate that ghrelin is up- and down-regulated in anorexia nervosa (AN) and obesity, which are also known to be accompanied by increased and reduced GH levels respectively. Ageing is associated with a gradual but progressive reduction in GH secretion, and by alterations in appetite and food intake. The role of ghrelin in the decline of somatotroph function and the anorexia of ageing is unknown. To investigate the influence of age on circulating levels of ghrelin, a total of 19 young and old normal weight subjects (Y-NW, n=12; O-NW, n=7), six patients with active AN (A-AN), and seven patients with morbid obesity (OB) were studied. In addition to fasting plasma ghrelin concentrations, baseline serum TSH, IGF-I and insulin levels were measured. Mean plasma ghrelin concentrations in A-AN or OB were higher and lower respectively than those present in Y-NW. Interestingly, mean plasma ghrelin concentrations in O-NW were significantly lower than those present in Y-NW and superimposable on those of OB. The mean fasting plasma ghrelin concentrations in all groups of subjects were negatively correlated with body mass index and serum insulin levels, but not with TSH and IGF-I levels. This study provides evidence of an age-related decline of plasma ghrelin concentrations, which might explain, at least partially, the somatotroph dysregulation and the anorexia of the elderly subject.

Adolescent↗

PubMed2001

The occurrence of E. coli O157:H7 in South African water sources intended for direct and indirect human consumption.

The occurrence of Escherichia coli O157:H7 in selected water samples in South Africa was investigated. The chromogenic Rainbow agar O157 medium designed for the rapid identification of E. coli O157:H7 was used for the detection of these organisms in various river-water samples in the Vaal Barrage Reservoir drainage basin of South Africa. A total of 204 samples were obtained from 15 sites where water was used for direct and indirect human consumption. Samples were filtered through Gelman filter-units and incubated on Rainbow agar O157 which produced different colours according to the bacterial chromogenic properties. Six hundred and sixty-three suspected E. coli O157:H7 colonies, with colours ranging between dark blue, grey and black, were subcultured onto sorbitol-MacConkey agar and screened for different virulence factors specific for E. coli O157:H7 and agglutination with anti-E. coli O157 antiserum. The results indicated that none of the suspected colonies contained all of the virulence factors necessary to classify them as E. coli O157:H7. None of these organisms agglutinated with antisera against E. coli O157. The probability of being infected with E. coli O157:H7 from direct or indirect consumption of these river water sources is therefore low. Some samples did, however, contain enterohaemorrhagic E. coli virulence properties, such as Stx1, Stx2 and enterohaemolysin, which might impose a health risk if ingested.

Colony Count, Microbial↗

PubMed2001

Hexarelin, but not growth hormone, protects heart from damage induced in vitro by calcium deprivation replenishment.

The effects of hexarelin, a growth hormone (GH) secretagogue, and human GH on the mechanical and metabolic changes measured in isolated rat hearts submitted to 5 min of Ca2+ deprivation followed by reperfusion with Ca2+-containing medium, the so-called calcium paradox phenomenon, were studied. Hexarelin (80 microg/kg bid, subcutaneously) administered for 7 d to male rats effectively antagonized the sudden increase in resting tension measured in vitro on Ca2+ repletion. Moreover, during Ca2+ repletion the release of creatine kinase activity (an index of cell damage) in the perfusate of these hearts was reduced up to 40% compared with controls. By contrast, administration of hexarelin for 3 d or GH (400 microg/kg bid, subcutaneously) for 7 d did not affect the mechanical and metabolic alterations induced by the calcium paradox. To assess its direct and acute cardiac effects, hexarelin (8 microg/mL) was perfused in vitro in recirculating conditions for 60 min through the hearts of normal rats. In this case, hexarelin did not stimulate heart contractility and failed to prevent ventricular contracture upon Ca2+ readmission, whereas diltiazem, a Ca2+channel blocker, effectively antagonized the calcium paradox phenomenon. We conclude that short-term in vivo exposure to hexarelin, but not GH, enables cardiac myocyites to prevent cytoplasmatic electrolytic unbalance and to control intracellular Ca2+ gain, two functions largely impaired during the calcium paradox phenomenon. Moreover, because the effect of hexarelin is not acute but dependent on the length of in vivo treatment, we suggest that it requires modifications of myocardiocyte physiology.

Animals↗

PubMed2001

Contrasting effects of nitric oxide on food intake and GH secretion stimulated by a GH-releasing peptide.

OBJECTIVE: Among the many actions of nitric oxide (NO) are those on endocrine and feeding behaviour. Based on NO involvement in the GH-releasing effect of the GH-releasing peptides (GHRPs) and the reported orexigenic activity of these compounds, we sought to evaluate the effect of the combined administration of a long-acting NO donor, molsidomine, and the newly synthesized GHRP EP92632 on food intake and GH secretion in rats. Moreover, to verify the specificity of a potential NO involvement, we evaluated whether or not the effects of GHRPs were abolished by a pre-treatment with an inhibitor of NO synthase, N-nitro-arginine-methyl-ester (NAME). METHODS: In the food intake experiments, adult Sprague-Dawley male rats underwent acute administration of: (1) EP92632 (160 microg/kg, s.c.); (2) molsidomine (100 mg/kg, i.p.); (3) EP92632+molsidomine; (4) l-NAME (40 and 60 mg/kg, i.p.); (5) EP92632+l-NAME (60 mg/kg, i.p.); (6) EP92632+molsidomine+l-NAME (60 mg/kg, i.p.); and (7) 0.9% saline (0.1 ml/kg, i.p.). After treatments, the cumulative food intake in the 6 post-treatment hours was carefully evaluated. In the neuroendocrine experiments, rats were given the same compounds according to the above reported schedule, except for the use of one dose of NAME (60 mg/kg, i.p.) and a lower EP92632 dose (80 microg/kg, s.c.), and were sampled via atrial cannula. RESULTS: EP92632 significantly stimulated food intake, an effect which was further enhanced by molsidomine, though the latter did not elicit per se any orexigenic effect. l-NAME given alone significantly decreased food intake and abolished the orexigenic effect of the GHRP and the enhancing effect of molsidomine. Plasma GH levels increased significantly following administration of EP92632 but, in contrast to the food intake experiments, molsidomine significantly inhibited both basal and EP92632-stimulated GH secretion; moreover, NAME had a biphasic effect on the EP92632-stimulated GH release: initially inhibitory and then, from 45 min on, stimulatory. NAME did not affect basal GH levels but, surprisingly, combined administration of molsidomine and NAME induced a striking inhibition of both basal and the peptide-stimulated GH release. CONCLUSIONS: In summary, these data indicate that NO in the rat is physiologically involved in a stimulatory way in the GHRP-mediated effect on food intake, but exerts a dual action, probably stimulatory at hypothalamic and inhibitory at pituitary levels, on basal and GHRP-stimulated GH secretion.

Animals↗

PubMed2001

Growth hormone (GH) rebound rise following somatostatin infusion withdrawal: studies in dogs with the use of GH-releasing hormone and a GH-releasing peptide.

OBJECTIVE: Evidence has been presented that in both animals and humans the rebound secretion of growth hormone (GH) following withdrawal of an infusion of somatostatin (SS) is due to the functional activation of the hypothalamic GH-releasing hormone (GHRH) neurons of the recipient organism. Based on this premise, this study has sought to assess the existence of functional interactions between endogenous GHRH released by a SS infusion withdrawal (SSIW) and growth hormone-releasing peptides (GHRPs), a class of compounds allegedly acting via GHRH. METHODS: Five young dogs (3 to 4 years old, 2 male and 3 female) were administered, on different occasions, three consecutive intravenous boli of physiological saline (0.1 ml/kg), or GHRH (2 microg/kg), or EP92632 (125 microg/kg), a GHRP compound, or GHRH plus EP92632 at the end of three cycles of 1-h SS infusions (8 microg/(kg x h)) or during a 6-h infusion of saline. RESULTS: Under saline infusion (SALI), plasma GH levels were unaltered, whereas each SSIW cycle was followed by similar GH secretory episodes. Administration of the first GHRH bolus under SALI induced a rise in plasma GH concentrations slightly higher than that induced by the first cycle of SSIW, but the GH response to the second and third GHRH boli was similar to that after SSIW. Following SSIW, the response to the first bolus of GHRH was higher than that during SALI, but the second and third cycles of SSIW induced GH responses similar to those evoked by the GHRH bolus. During SALI, administration of the first bolus of EP92632 induced a rise in plasma GH which was higher than that induced by the first GHRH bolus, the second bolus elicited a GH peak of lesser amplitude and there was a partial restoration of the GH response to the third peptide bolus. SSIW strikingly enhanced the GH release to the first EP92632 bolus, a pattern also present, although to a lesser extent, with the second and third cycles of SSIW. Under SALI, combined administration of GHRH and EP92632 had a synergistic effect on GH release, but a progressive reduction was present in the GH response to the second and third GHRH plus EP92632 boli. SSIW increased only weakly the GH response to the first co-administration of the peptides over that present after administration of EP92632 alone, and did not induce a GH response higher than that present during SALI when the second bolus of the peptides was administered; after the third SSIW a GH rise higher than that present during SALI was elicited by the combined administration of the peptides. CONCLUSIONS: (i) the uniformity of the GH rebound responses to multiple cycles of SSIW may indicate that the latter activate a physiological mechanism which mimics that normally controlling GH pulse generation; (ii) EP92632 elicits, under our experimental conditions, a plasma GH rise higher than that induced by GHRH; (iii) SSIW enhances the GH response to EP92639 alone, to an extent reminiscent of that following combined administration of GHRH and EP92632. This pattern reinforces the view that SSIW elicits release of endogenous GHRH, and infers that the GHRP challenge after SSIW may be exploited in humans to distinguish between healthy and GH-deficient adults.

Animals↗

PubMed2001

[Steroids, cognitive processes and aging].

Adrenal steroids, besides acting on the pituitary and the hypothalamus to exert classical feedback activity, can also have endocrine and extra-endocrine actions at the level of sub-cortical areas, as the hippocampus and the amygdala, involved in cognition and effectiveness. Acting on the hippocampus, an area particularly equipped with specific receptor sites, adrenal steroids exert either a feedback inhibition on their own secretion or a morphological and functional age-related deterioration of this target area. Loss of hippocampal neurons and corticosteroid receptors with ageing endangers the feedback inhibitory action of the steroids, and induces an over-exposition of the hippocampus to their detrimental action, enhancing the vulnerability of the neuronal cells to metabolic stimuli (hypoxia, hypoglycemia). Hence, either in the physiological ageing of the brain as well as in age-related neurological diseases or psychiatric diseases, harboring a primary neuro-anatomical-functional alteration of the hippocampus, or when the hippocampus is over-exposed to adrenal steroids, a cohort of cognitive and behavioral alterations may be partly due to adrenal gland hyperfunction. Gonadal steroids exert effects on the CNS which go far beyond regulation of gonadotropin secretion and sexual function, though their action is opposite to that of adrenal steroids. Estrogens stimulate hippocampal synaptogenesis, enhance cholinergic neurotransmission, possess anti-oxidative and anti-amiloidogenic properties, dilate cerebral vessels and have platelet anti-aggregating activity. One is led to postulate that the dramatic decrease of estrogen secretion at menopause should increase the vulnerability of the CNS by the many factors contributing to neurodegeneration associated to brain ageing or Alzheimer disease.

Adrenal Cortex Hormones↗

PubMed2000

Hexarelin, a growth hormone secretagogue, protects the isolated rat heart from ventricular dysfunction produced by exposure to calcium-free medium.

The effect of hexarelin, a potent synthetic growth hormone (GH)-secretagogue, and of human GH were studied on the mechanical and metabolic changes elicited by the calcium-paradox phenomenon in isolated rat hearts submitted to 5 min Ca(2+)-depletion followed by reperfusion with reintegrated Ca(2+)medium. Hexarelin, (80 microg kg(-1)s.c.) administered to normal male young rats for 3 and 7-day, time-dependently antagonized the sudden increase in resting tension of the isolated perfused hearts upon Ca(2+)-repletion. The beneficial effect of hexarelin was particularly evident in the 7-day treatment. In this instance, ventricular contraction peaked at 30 +/- 2 mmHg (controls, 76 +/- 7 mmHg) and the recovery of left ventricular developed pressure (LVDP) was two times higher (P<0.001) than that recorded in controls (LVDP, 29 +/- 2 mmHg). Moreover, the release of creatine kinase into the heart effluent during Ca(2+)-repletion was reduced by 40% (P<0.001) as compared to controls. The protecting activity of hexarelin against the damage induced by calcium-paradox in the heart was apparently divorced from any stimulation of the GH/insulin-like growth factor (IGF) axis, since plasma and heart concentrations of IGF-1 were similar to those measured in control rats. In contrast to hexarelin, administration of GH (400 microg kg(-1) s.c.) for 7 days did not affect the mechanical and metabolic manifestations of calcium-paradox in the perfused rat hearts. Hexarelin (8 microg ml(-1)) perfused for 60 min through the hearts in recirculating conditions did not modify heart contractility and failed to prevent ventricular hypercontractility developed on Ca(2+)-readmission. In conclusion, the mode of action of hexarelin in protecting the rat heart from calcium-paradox events is presently unknown; it would seem, however, that only prolonged exposure to hexarelin makes myocardial cells competent to maintain cytoplasmatic electrolyte balance and to control of Ca(2+)gain, two functions that are impaired during the 'calcium-paradox' phenomenon.

Animals↗

PubMed2000

[Delirium after vascular surgery interventions. Intermediate-term results of a prospective study].

INTRODUCTION: Postoperative delirium is a common psychic disturbance occurring acutely after various surgical procedures and typically presenting with a fluctuating course. These patients' recovery takes longer. In this study we analyze the incidence of postoperative delirium in patients undergoing vascular surgery and try to identify risk factors for its development. METHODS: Patients undergoing elective arterial operations were included. Their medical history, the specific vascular diagnosis and operation performed, the medication and laboratory data were monitored. Additionally the patients were preoperatively interviewed by a psychiatrist. Intraoperatively the drugs, infusions, possible transfusions, blood gases and pressures were monitored, as were the times of surgery and anesthesia. Postoperatively patients were seen daily by the psychiatrist and the surgeon for at least 7 days. Postoperative delirium was diagnosed according to DSM IV criteria, and mild, moderate and severe delirium were distinguished. RESULTS: Fifty-four patients entered the study. Twenty-one (38.9%) developed postoperative delirium (11 mild, 2 moderate, 8 severe). Patients with aortic operations developed delirium more frequently than those with non-aortic procedures(55.5 vs 22.2%, n = 27 each). Some preexisting diseases (hearing disturbance) increased the probability of postoperative delirium, while age was not identified as a risk factor. General psychopathological and depressive disturbances increased the likelihood of postoperative delirium. Patients who had a severe intraoperative course developed postoperative delirium more frequently. This was not seen in the absolute time of surgery or anesthesia nor in the intraoperative development of blood pressure or intraarterial gases, which did not differ between patients with and without postoperative delirium. More reliable parameters were an increased intraoperative need for crystalloid volume, intra- or postoperatively decreased hemoglobin values (Hb < 10 g/dl) and the development of acidosis that had to be treated. Patients with delirium had serious complications more often (8/21 = 38.1% vs 6/33 = 18.2%) and needed Intensive Care treatment longer (2.7 vs 2.1 days, only aortic surgery 3.2 vs 2.4 days). CONCLUSIONS: Postoperative delirium after vascular surgery is frequent. Patients undergoing aortic surgery, with specific concomitant medical disease, psychopathological disturbances and a severe intraoperative course, are at risk of developing postoperative delirium.

Aged↗

PubMed2000

Gamma-hydroxybutyric acid and growth hormone secretion studies in rats and dogs.

Gamma-hydroxybutyric acid, a gamma-aminobutyric acid metabolite, and baclofen, a gamma-aminobutyric acid B agonist, are endowed with a small growth hormone-releasing activity in human beings. In this study, we have investigated the reciprocal interactions of gamma-hydroxybutyric acid and the gamma-aminobutyric acid B system by evaluating the growth hormone-releasing activity of the two compounds and their respective antagonists in in vivo and in vitro experiments performed in rats and dogs. In in vivo experiments, neither gamma-hydroxybutyric acid (25, 100, 150, and 300 mg/kg, SC) nor baclofen (0.25, 1, 2, 4, and 8 mg/kg, SC) significantly modified growth hormone secretion in 9-day-old rat pups. Similarly, no growth hormone and prolactin release was observed in adult anesthetized rats after administration of gamma-hydroxybutyric acid (100 mg/kg, IP) or baclofen (10 mg/kg IP). Equally ineffective on the somatotropic response was the administration of gamma-hydroxybutyric acid (200 mg/kg, IP) alone or associated with its specific receptor antagonist NCS-382 (150 mg/kg, IP) given to adult anesthetized rats. In addition, a toxicological dose of gamma-hydroxybutyric acid (1500 mg/kg, IP) did not alter baseline growth hormone levels in adult conscious rats. gamma-Hydroxybutyric acid (50 mg/kg, IP) given for 10 days to adult conscious rats did not alter the growth hormone response to the same gamma-hydroxybutyric acid dose given acutely. In conscious dogs, gamma-hydroxybutyric acid (20 and 50 mg/kg, IV) and baclofen (0.15, 0.30 mg/kg, IV) also were ineffective in stimulating growth hormone secretion. In this species, growth hormone response to hexarelin (31.25 microg/kg, IV), a potent growth hormone-releasing peptide, was not modified by coadministration of gamma-hydroxybutyric acid (50 mg/kg, IV). In in vitro experiments, increasing doses of gamma-hydroxybutyric acid (10(-7), 10(-5), and 10(-3) M) did not alter growth hormone concentrations in media of rat pituitary cell cultures. In contrast, growth hormone-releasing hormone (10(-7) M) induced a significant growth hormone release into the media. In conclusion (1) gamma-hydroxybutyric acid is not an effective growth hormone secretagogue; (2) the reciprocal functional interactions between gamma-hydroxybutyric acid and the gamma-aminobutyric acid B system could not be investigated, due to the ineffectiveness of gamma-hydroxybutyric acid and baclofen to stimulate growth hormone release; and (3) short-term administration of gamma-hydroxybutyric acid does not induce adverse effects amenable to activation of the somatotropic function.

Adrenergic alpha-Agonists↗

PubMed2000

Differential orexigenic effects of hexarelin and its analogs in the rat hypothalamus: indication for multiple growth hormone secretagogue receptor subtypes.

We have previously reported that hexarelin and some of its analogs, including EP 50885, stimulated GH secretion and feeding after systemic administration in the rat, whereas EP 40904 selectively stimulated food intake and EP 40737 only GH release. The precise mechanism of growth hormone-releasing peptides (GHRPs) actions is still unclear, but the integrity of the arcuate nucleus of the hypothalamus (ARC) appears crucial for their endocrine effects. To better characterize the site(s) and mechanisms(s) of the orexigenic action of GHRPs, we have investigated their effects after infusion into the arcuate, paraventricular, ventromedial and medial preoptic areas of the hypothalamus. Food intake was measured for 60 min following injection of the test compound (2 microg/rat). Hexarelin, EP 40904 and EP 50885 had significant orexigenic effects after injection into the ARC. A specific NPY antagonist significantly inhibited the effect of hexarelin, whereas a GHRH antagonist was ineffective. In the paraventricular nucleus, only EP 50885 stimulated feeding, whereas all peptides were ineffective in the ventromedial nucleus and medial preoptic area. Taken altogether, these results demonstrate that GHRPs are endowed with site-specific orexigenic actions and that endogenous NPY, but not GHRH, mediates these effects. The additional orexigenic action of EP 50885 in the paraventricular nucleus suggests the existence of a GHRP receptor subtype different from the already cloned one.

Animals↗