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Biomedical subjects

R Landgraf

Publications and source records attributed to R Landgraf.

At least 109 records · Page 6Linked to original sources
PubMed1998

Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV-1-infected patients.

BACKGROUND: The use of protease inhibitors in the treatment of HIV-1 infection is associated with the new onset of diabetes mellitus, hyperlipidaemia and lipodystrophy. It is unclear whether these findings are coincidental or whether they reflect a causative effect of protease inhibitors. OBJECTIVE: To evaluate the effect of treatment with protease inhibitors on insulin sensitivity, oral glucose tolerance and serum lipids in HIV-infected patients in order to determine whether treatment with protease inhibitors can cause peripheral insulin resistance. DESIGN: Cross-sectional controlled study in HIV-infected patients treated with protease inhibitors to assess insulin sensitivity, oral glucose tolerance and changes in serum lipids. METHODS: Sixty-seven patients treated with protease inhibitors, 13 therapy-naive patients and 18 HIV-negative control subjects were tested for insulin sensitivity (intravenous insulin tolerance test). In a subgroup of 24 treated patients, oral glucose tolerance was determined. Serum lipids prior to and under treatment with protease inhibitors were compared. RESULTS: Patients on protease inhibitors had a significantly decreased insulin sensitivity when compared with therapy-naive patients (median, 75 and 156 micromol/l/min, respectively; P < 0.001). All treated patients with impaired (n=4) or diabetic (n=9) oral glucose tolerance, and four out of 11 patients with normal glucose tolerance showed peripheral insulin resistance; all therapy-naive patients had normal insulin sensitivity. Treatment with protease inhibitors led to a significant increase in total triglycerides and cholesterol in the 67 treated patients (median increase, 113 and 37 mg/ml, respectively). CONCLUSION: Treatment with protease inhibitors is associated with peripheral insulin resistance, leading to impaired or diabetic oral glucose tolerance in some of the patients, and with hyperlipidaemia. Overall, there is a large variation in the severity and clinical presentation of protease inhibitor-associated metabolic side-effects.

Adult↗
PubMed1998

Olfactory bulb norepinephrine depletion abolishes vasopressin and oxytocin preservation of social recognition responses in rats.

Male rats were implanted bilaterally with cannulae directed at the olfactory bulbs and infused with either vehicle or 6-OHDA to selectively deplete norepinephrine concentrations at this site. At 5-7 days following this treatment, these animals received a bilateral infusion of either arginine vasopressin (AVP) or oxytocin (OXT) through these same guide cannulae and were then tested for their capacity to maintain social recognition responses. Neither infusion of AVP nor OXT were able to preserve recognition responses in the animals treated with 6-OHDA. In contrast, comparably tested animals who received a vehicle infusion showed clear recognition responses following either the AVP or OXT infusion. These results suggest that this capacity for these neuropeptides to preserve social recognition responses is mediated through the norepinephrine system of the olfactory bulb.

Animals↗
PubMed1998

Swim stress triggers the release of vasopressin within the suprachiasmatic nucleus of male rats.

The hypothalamic suprachiasmatic nucleus (SCN) is the predominant pacemaker of the mammalian brain that generates and controls circadian rhythms of various endocrine and behavioral processes. Different lines of evidence suggest that stress interferes with the maintenance of such rhythms. As a first approach to investigate whether the neuropeptide arginine vasopressin (AVP), which shows circadian rhythms of synthesis and release within the SCN, might contribute to this stress-induced alterations in circadian rhythms, we monitored acute effects of swim stress on the intra-SCN release of AVP in male rats by means of the microdialysis technique. A 10-min forced swimming session triggered a marked but relatively short-lasting increase in the intranuclear release of AVP (to approx. 440%). This effect was restricted to the area containing predominantly somata and dendrites of vasopressinergic neurons, since no changes in AVP release could be measured in one of their major projection areas, the nucleus of the dorsomedial hypothalamus. Our data provide evidence that the amount of AVP released within the SCN can vary widely not only in accordance with AVP's intrinsically regulated circadian rhythm but also in response to a physiologically relevant stressor. In this way, the neuropeptide may contribute to the regulation of endocrine and behavioral rhythms particularly in challenging situations associated with resettings of the endogenous clock.

Animals↗
PubMed1998

Attenuated neuroendocrine responses to emotional and physical stressors in pregnant rats involve adenohypophysial changes.

1. The responsiveness of the rat hypothalamo-pituitary-adrenal (HPA) axis and hypothalamo-neurohypophysial system (HNS) to emotional (elevated plus-maze) and physical (forced swimming) stressors and to administration of synthetic corticotrophin-releasing hormone (CRH) was investigated during pregnancy and lactation. In addition to pregnancy-related adaptations at the adenohypophysial level, behavioural responses accompanying the neuroendocrine changes were studied. 2. Whereas basal (a.m.) plasma corticosterone, but not corticotrophin (adrenocorticotrophic hormone; ACTH), levels were increased on the last day (i.e. on day 22) of pregnancy, the stress-induced rise in both plasma hormone concentrations was increasingly attenuated with the progression of pregnancy beginning on day 15 and reaching a minimum on day 21 compared with virgin control rats. A similar attenuation of responses to both emotional and physical stressors was found in lactating rats. 3. Although the basal plasma oxytocin concentration was elevated in late pregnancy, the stress-induced rise in oxytocin secretion was slightly lower in day 21 pregnant rats. In contrast to vasopressin, oxytocin secretion was increased by forced swimming in virgin and early pregnant rats indicating a differential stress response of these neurohypophysial hormones. 4. The blunted HPA response to stressful stimuli is partly due to alterations at the level of corticotrophs in the adenohypophysis, as ACTH secretion in response to CRH in vivo (40 ng kg-1, i.v.) was reduced with the progression of pregnancy and during lactation. In vitro measurement of cAMP levels in pituitary segments demonstrated reduced basal levels of cAMP and a lower increase after CRH stimulation (10 nM, 10 min) in day 21 pregnant compared with virgin rats, further indicating reduced corticotroph responsiveness to CRH in pregnancy. 5. The reduced pituitary response to CRH in late pregnancy is likely to be a consequence of a reduction in CRH receptor binding as revealed by receptor autoradiography. [125I] CRH binding in the anterior pituitary was significantly reduced in day 11, 17 and 22 pregnant rats compared with virgin controls. 6. Anxiety-related behaviour of the animals as revealed by the time on and entries into the open arms of the elevated plus-maze was different between virgin and pregnant rats with decreased number of entries indicating increased anxiety with the progression of pregnancy (except on pregnancy day 18). The emotional behaviour, however, was not correlated with the neuroendocrine responses. 7. The results indicate that the reduced response of the HPA axis to stressors described previously during lactation is already manifested around day 15 of pregnancy in the rat and involves physiological adaptations at the adenohypophysial level. However, alterations in stressor perception at higher brain levels with the progression of pregnancy may also be involved.

Acclimatization↗
PubMed1998

Cytotoxicity and specificity of directed toxins composed of diphtheria toxin and the EGF-like domain of heregulin beta1.

As a step in the design of directed toxins, aimed at cells that overexpress HER receptors, particularly breast carcinoma cells, we studied the properties of a chimera of diphtheria toxin (DT) and heregulin beta1. The EGF-like growth hormone heregulin is a ligand for the HER3 and HER4 receptors and their heterodimers with HER2. The 60-residue EGF-like domain (hrg) of heregulin elicits a biological response and binds to these receptors primarily through its N terminus. We tested a fusion protein in which hrg replaces the C-terminal receptor-binding domain of DT (DT(389)hrg) and an alternative design in which this domain is fused to the N terminus of DT(389). Of those two constructs, the N-terminal fusion was not active as a directed toxin but elicited a growth response. The C-terminal fusion of hrg to DT(389) yielded a functional toxin and showed cell line specific cytotoxicity that is consistent with heregulin specificity. The binding of hrg to its cognate receptor is not impaired as shown by receptor activation, direct binding, and competition with free hrg. Cytotoxicity is dependent on high-affinity binding of DT(389)hrg to HER3 and HER4 receptors and is not mediated by HER2 overexpression alone. For those cell lines exhibiting high-affinity binding sites, the level of cytotoxicity correlates with the rate of internalization. Thus DT(389)hrg chimeras offer a possible avenue toward directed toxins against cells that overexpress HER receptors.

Binding Sites↗
PubMed1998

Human insulin analogue [LYS(B28), PRO(B29)]: the ideal pump insulin?

The short-acting insulin analogue lispro ([LYS(B28), PRO(B29)] is absorbed from the subcutis more rapidly than soluble insulin (S). To compare the clinical effectiveness of lispro vs S, 11 Type 1 patients using continuous subcutaneous insulin infusion (CSII) therapy (6 F, 5 M, age 30 +/- 2.5 years, diabetes duration 14 +/- 1.0 years, BMI 24.0 +/- 0.8 kg m(-2), HbA1c 6.5 +/- 0.2%) were studied in an open, randomized, crossover study for 6 months (3 months lispro and 3 months S or vice versa). During lispro treatment mean fasting and 2 h postprandial blood glucose were lower compared to the S phase (fasting 6.5 +/- 0.4 vs 7.5 +/- 0.4 mmol l(-1) (NS), postprandial 6.8 +/- 0.3 vs 8.3 +/- 0.3 mmol l(-1), p = 0.03). In patients treated first with lispro HbA1c levels improved from 6.3 +/- 0.2% to 5.7 +/- 0.3%; On reversion to S HbA1c increased to 6.2 +/- 0.2%. In the group treated first with S, HbA1c fell (6.7 +/- 0.4% vs 6.5 +/- 0.3%) and then improved further to 6.3 +/- 0.3% with lispro. None of these changes were significant. There was no significant difference with respect to hypoglycaemic or other adverse events. It can be concluded that lispro in CSII therapy is safe and may improve postprandial glucose excursions.

Adult↗
PubMed1998

Release of vasopressin within the brain contributes to neuroendocrine and behavioral regulation.

In addition to its peripheral secretion from the neurohypophysis, the neuropeptide vasopressin (VP) is released within the mammalian brain from probably all parts of the neuronal membrane. In particular the development of brain microdialysis in vivo together with blood microdialysis or blood sampling provides the advantage of being able to reliably compare the dynamic release patterns into different compartments of the organism. The central VP release within hypothalamic (e.g., supraoptic, paraventricular and suprachiasmatic nuclei) and limbic (e.g., septum, amygdala) rat brain areas is stimulated by a variety of substances and stressors, including interleukin-1 beta, social defeat and forced swimming. Furthermore, it is characterized by positive and negative feedback mechanisms and the capacity of the VP system for co-ordinated or independent release, the latter being observed, for example, during social defeat. This emotional stressor, in contrast to exposure to a novel cage, increased VP release within the supraoptic nucleus, but not into plasma. This failure to release VP peripherally could be observed also during forced swimming, despite a dramatic rise in plasma osmolality and a markedly stimulated central release. In another series of experiments we studied the effects of centrally-released VP on cognitive and emotional aspects of behavior using reverse microdialysis for antagonist administration during the behavioral tests and antisense targeting to downregulate either VP or its local V1 receptor subtype. In this way, centrally (in particular septally) released VP could be shown to be causally involved in short-term memory and anxiety-related behavior. Furthermore, VP release within the hypothalamic paraventricular nucleus is likely to provide a negative tonus on the activity of the hypothalamic-pituitary-adrenocortical axis. This neuroendocrine effect together with cognitive, emotional and immunological effects of centrally released VP is thought to be essential to ensure adequate behavior of the animal during challenging situations and to contribute to the development of efficient coping strategies.

Animals↗
PubMed1998

Endogenous oxytocin is involved in short-term olfactory memory in female rats.

To investigate the involvement of oxytocin in their short-term lasting olfactory memory performance, adult female Wistar rats (n = 12) were tested for their juvenile discrimination abilities. As measured by their exploratory behavior towards juveniles, the adult rats were able to discriminate between a previously exposed juvenile and a novel one as long as the interval between the two exposures was less than 180 min. This ability was maintained across all days of the estrous cycle and was unaffected by intracerebroventricular administration of synthetic oxytocin (1 ng/5 microl Ringer's solution) or Ringer's solution immediately after the first exposure. However, treatment with the oxytocin receptor antagonist des-Gly-NH2 d(CH2)5[Tyr(Me)2Thr4]OVT interfered with the ability to establish this kind of olfactory memory although the vasopressin V1 receptor antagonist d(CH2)5Tyr(Me)AVP (100 ng/5 microl each) via the same route did not. This suggests that within a narrow range of concentrations endogenous oxytocin, but not vasopressin, is critically involved in short-term olfactory memory for juvenile conspecifics in female rats. These data are discussed in the light of sexual dimorphic brain development.

Animals↗
PubMed1998

Behavioural profiles of two Wistar rat lines selectively bred for high or low anxiety-related behaviour.

Over the past years, two breeding lines, derived originally from outbred Wistar rats, have been established that differ markedly and consistently in their anxiety-related behaviour in the elevated plus-maze. At the age of ten weeks, rats were tested once on the elevated plus-maze and the males and females displaying the most anxious and the least anxious behaviour were sib-mated to start a new generation of the high anxiety-related behaviour (HAB) and the low anxiety-related behaviour (LAB) lines, respectively. The resulting difference in emotionality between these two lines was also evident in an open field test and correlated with differences in the forced swim test. In the open field, the HAB rats tended to be less active and explored the central zone of the open field much less than the LAB animals. In the forced swim test, HAB rats started floating earlier, spent significantly more time in this immobile posture and struggled less than LAB rats. However, in an olfactory-cued social discrimination task there was no difference between male and female animals from either line. The overall performance in these various behavioural tests suggests that selective breeding has resulted in rat lines not only differing markedly in their innate anxiety-related behaviour in the plus-maze, but also in other stress-related behavioural performances, suggesting a close link between the emotional evaluation of a novel and stressful situation and an individual's coping strategy.

Animals↗
PubMed1998

The effects of infusion of arginine vasopressin, oxytocin, or their antagonists into the olfactory bulb upon social recognition responses in male rats.

In the present report, the peptides arginine vasopressin (AVP), oxytocin (OXT) or their respective antagonists were infused bilaterally into the olfactory bulb to assess their effects upon recognition responses. Recognition responses were determined in a social discrimination paradigm and consisted of measuring the amount of investigation directed to either the same (previously exposed) or novel juvenile rats under conditions in which clear recognition responses are either present as tested with a 30 min inter-exposure interval or absent as tested with a 120 min inter-exposure interval. Infusion of AVP or OXT resulted in preserved recognition responses, as tested with a 120 min inter-exposure interval, compared with that observed in vehicle-infused controls. When animals were infused with the AVP or OXT antagonists using two different doses and tested for the display of recognition as tested with the 30 min inter-exposure interval, no effects of these antagonists were obtained with either dose. These results demonstrate that the olfactory bulb represents an additional important central nervous system target site where these peptides can act to preserve social recognition responses. Moreover, our results suggest that the underlying mechanisms by which peptides function within the olfactory bulb differ as a function of whether they are involved with the display versus preservation of recognition responses.

Aging↗
PubMed1998

Enhanced morphine-induced behavioural effects and dopamine release in the nucleus accumbens in a transgenic mouse model of impaired glucocorticoid (type II) receptor function: influence of long-term treatment with the antidepressant moclobemide.

In vivo microdialysis experiments were conducted in transgenic mice with impaired glucocorticoid receptor function resulting from expression of antisense directed against glucocorticoid receptor messenger RNA. Basal corticosterone and serotonin levels in the nucleus accumbens of untreated transgenic mice were enhanced compared to control mice (B6C3F1). Following a systemic morphine injection (15 mg/kg) mesolimbic dopamine and serotonin release was markedly increased in transgenic mice compared to control mice and in parallel enhanced behavioural stimulation was observed in these animals. After pretreatment with the antidepressant moclobemide over a time period of eight weeks (15 mg/kg/day) elevated basal levels of both corticosterone and serotonin were normalized in transgenic mice. Furthermore, morphine-induced dopamine and serotonin release as well as behavioral stimulation were suppressed in transgenic mice and similar to that in control mice. The results indicate that impaired glucocorticoid receptor function influences the basal release of serotonin in the nucleus accumbens. This alteration has no effect on basal but on morphine-stimulated release of dopamine in the mesolimbic system. An enhanced sensitivity to the effects of morphine is apparently related to elevated brain corticosterone and serotonin levels and can be normalized by long-term antidepressant treatment.

Animals↗
PubMed1998

Dissociated central and peripheral release of vasopressin, but not oxytocin, in response to repeated swim stress: new insights into the secretory capacities of peptidergic neurons.

To investigate the effects of an ethologically-relevant stressor on central and peripheral release of arginine vasopressin and oxytocin, we forced adult male Wistar rats to swim for 10 min and simultaneously measured the release of the two peptides (i) within the hypothalamic supraoptic and paraventricular nuclei (by means of the microdialysis technique) and (ii) into the blood (by chronically-implanted jugular venous catheters). Forced swimming caused a significant rise in the release of arginine vasopressin and oxytocin within both the supraoptic nuclei (four-fold and three-fold, respectively) and the paraventricular nuclei (three-fold and four- to five-fold, respectively). Release patterns measured before, during and after repeated stress exposure on three consecutive days indicated that, at the level of the hypothalamus, the two neuropeptides are critically involved in the rats' stress response in a peptide-, locus- and stress-specific manner. Particularly, despite a general reduction of the recovery of the microdialysis probes over the time, the release of arginine vasopressin within the paraventricular nuclei and of oxytocin within the supraoptic nuclei tended to increase upon repeated stress exposure. Measurement of plasma peptide concentrations revealed that the central release of oxytocin was accompanied by a secretion of this peptide into the systemic circulation. In contrast, arginine vasopressin, assayed in the same plasma samples, failed to respond to the stressor. The latter finding is consistent with a dissociated release of the neuropeptide from different parts of a single neuron (soma/dendrites vs axon terminals). It provides evidence that under physiological conditions plasma hormone levels do not necessarily reflect the secretory activity of central components of the respective neuropeptidergic system.

Animals↗
PubMed1998

Increased basal activity of the hypothalamo-pituitary-adrenal axis during pregnancy in rats bred for high anxiety-related behaviour.

In order to test the hypothesis that prenatal hormones influence the emotional maturation of the offspring, the hypothalamo-pituitary-adrenal (HPA) axis activity was studied at the end of pregnancy in two rat breeding lines differing consistently in their innate anxiety-related behaviour in the elevated plus-maze. Virgin and pregnant rats were fitted with a chronic jugular vein catheter and tested 5 days later. The high basal level of anxiety-related behaviour (HAB) described in males and females of the HAB breeding line persists in pregnancy as indicated by a significantly reduced number of entries into and time spent on the open arms of the elevated plus-maze between days 18 and 20 of pregnancy compared with pregnant rats of the breeding line with low anxiety-related behaviour (LAB). In general, an increase in anxiety was found in both breeding lines in pregnancy compared with the respective virgin controls. With respect to HPA axis activity, increased basal levels of adrenocorticotropin (ACTH) and corticosterone have been found in pregnant rats of the HAB line compared with pregnant LAB rats. ACTH and corticosterone secretion in response to emotional and complex physical stressors (exposure to the elevated plus-maze and forced swimming, respectively) did not differ between virgin and pregnant rats of either breeding line. However, independent of the inborn emotionality of the animals, a general attenuation in the HPA axis response to stressors and to exogenous CRH could be confirmed in pregnant rats. The basal and stress-induced activity of the hypothalamo-neurohypophysial system secreting oxytocin and vasopressin was also tested, and no differences were found relating to the emotionality or reproductive state of the animals except for a reduced vasopressin secretion in pregnant HAB rats after forced swimming. The elevated basal activity of the HPA axis, including enhanced circulating concentrations of corticosterone in pregnant HAB rats, may influence both the neuroendocrine and emotional development of their offspring. Thus, the passing-on of maternal behavioural characteristics via prenatal, hormonal 'imprinting' has to be considered as a possible contribution to emotional maturation during an individual's development.

Adrenocorticotropic Hormone↗
PubMed1998

Behavioral, physiological, and neuroendocrine stress responses and differential sensitivity to diazepam in two Wistar rat lines selectively bred for high- and low-anxiety-related behavior.

Two Wistar rat lines, selectively bred for high-anxiety-related behavior (HAB) and low-anxiety-related behavior (LAB) in the elevated plus-maze test, were tested for the susceptibility of their behavioral characteristics to anxiolytic treatment and for their endocrine and physiological reactivity to different stressors. Injection of 1 mg/kg diazepam failed to affect line differences in coping strategy but resulted in a marked (20-fold) decrease in plus-maze anxiety in HAB rats; whereas, the anxiolytic effect was less pronounced in LAB animals. Biotelemetrical measurements revealed that HAB and LAB rats do not significantly differ in their baseline body temperature, locomotor activity, food and water intake, or in stress-induced alterations of the diurnal rhythms in these parameters. However, line differences were found in acute changes in body temperature and locomotor activity following stress exposure, LAB rats responding with a greater, albeit shorter, increase in body temperature and activity than HAB animals. Basal ACTH and corticosterone plasma levels as well as pituitary reactivity to intravenously administered CRH (40 ng/kg) were similar in both lines, although, especially in response to plus-maze exposure, HAB rats tended toward higher ACTH secretion than LAB rats. These data confirm that animals with high or low basal levels of anxiety may be a promising model for studying the mechanisms of action of anxiolytic substances. Nevertheless, the endocrine findings support the notion that the reactivity of the hypothalamo-pituitary-adrenocortical system and anxiety-related behavior can be regulated independently.

Adrenocorticotropic Hormone↗
PubMed1998

Scission of DNA at a preselected sequence using a single-strand-specific chemical nuclease.

BACKGROUND: We were interested in developing a protocol for cleaving large DNAs specifically. Previous attempts to develop such methods have failed to work because of high levels of nonspecific background scission. RESULTS: R-loop formation was chosen for sequence-specific targeting, a method of hybridization whereby an RNA displaces a DNA strand of identical sequence in 70% formamide using Watson-Crick base-pairing, leading to a three-stranded structure. R-loops are stabilized in aqueous solution by modifying the bases with chemical reagents. The R-loop was cleaved using a novel nuclease prepared from the Thr48-->Cys mutant of the single-strand-specific M-13 gene V protein (GVP), which was alkylated with 5-(iodoacetamido-beta-alanyl)1,10-phenanthroline. The cleavage products of the pGEM plasmid were cloned in to the pCR 2.1-TOPO vector. Adenovirus 2 DNA (35.8 kb; tenfold larger than the pGEM plasmid) was also cleaved quantitatively at a preselected sequence. CONCLUSIONS: A new method for cleaving duplex DNA at any preselected sequence was developed. The cleavage method relies on the chemical conversion of M-13 GVP into a nuclease, reflecting GVP's specificity for single-stranded DNA. The GVP chimera is the first example of a semisynthetic secondary structure specific nuclease. The chemical nuclease activity of 1,10-phenanthroline-copper is uniquely suited to this technique because it oxidizes the deoxyribose moiety without generating diffusible intermediates, providing clonable DNA fragments. The protocol could be useful in generating large DNA fragments for mapping the contiguity of probes or defining the exon-intron structure of transcription units.

Adenoviridae↗
PubMed1998

Cardiovascular risk profile after simultaneous pancreas and kidney transplantation.

The positive influence of simultaneous pancreas and kidney transplantation (PKT) on the development of diabetic microvascular lesions is well established. On the other hand, little is known on its impact on diabetic macrovascular disease, which is still the major cause of death in diabetes, including patients after PKT. In order to evaluate the influence of PKT on the cardiovascular risk profile, we performed a cross-sectional study on 55 patients. Special attention was given to the hemorheological parameters fibrinogen and plasma viscosity, two important cardiovascular risk factors, which so far have found no attention in the field of PKT research. The patients were subdivided into three groups according to their graft function: group 1-26 patients after successful PKT (no insulin dependency, serum creatinine <2 mg%), group 2-23 patients after PKT and rejection of the pancreas graft (insulin dependency, serum creatinine <2 mg%), group 3-6 patients after PKT with pancreas rejection and renal insufficiency (insulin dependency, serum creatinine >2 mg%, no dialysis). There was a high prevalence of arterial hypertension after PKT (group 1: 65%, group 2: 70%, group 3: 100%). Serum lipids were in the normal range as long as renal function was intact. In renal insufficiency, however, LDL-cholesterol and triglycerides were significantly elevated (p < 0.05). Fibrinogen was significantly raised after PKT (p < 0.001), as was plasma viscosity when the pancreas graft was rejected (p < 0.02). There was a tendency towards elevated fibrinogen levels with decreasing graft function. In conclusion, a number of cardiovascular risk factors were identified in patients after PKT, predominantly arterial hypertension and impaired hemorheology, with elevated fibrinogen levels and plasma viscosity. There is a further enhancement with decreasing graft function.

Adult↗