Biomedical subjects

M A Smith

Publications and source records attributed to M A Smith.

At least 163 records · Page 9Linked to original sources

PubMed2000

DNA methylation, ageing and ribosomal genes activity.

DNA methylation is an epigenetic mechanism controlling of gene expression. We studied the effect of a demethylation agent 5-azacytidine, on ribosomal gene activity observed by Nucleolus Staining Giemsa in the chromosomes of eight Alzheimer's disease patients, eight elderly healthy individuals and eight young healthy controls. Metaphase cells were obtained from lymphocyte cultures. All the acrocentric chromosome pairs were analyzed using G banding followed by Nucleolus Staining Giemsa banding in the same cell. The Alzheimer's disease patients and elderly healthy control did not show a variation in the transcriptional activity of ribosomal genes with or without 5-azacytidine treatment, whereas the young control group showed an increase in this activity with the treatment.

Adult↗

PubMed2000

Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats.

Insulin and leptin receptors are present in hypothalamic regions that control energy homeostasis, and these hormones reduce food intake and body weight in lean, but not obese, Zucker rats. Here we demonstrate that insulin, like leptin, hyperpolarizes lean rat hypothalamic glucose-responsive (GR) neurons by opening KATP channels. These findings suggest hypothalamic K ATP channel function is crucial to physiological regulation of food intake and body weight.

Adenosine Triphosphate↗

PubMed2000

Differential regulation of neuropeptide Y mRNA expression in the arcuate nucleus and locus coeruleus by stress and antidepressants.

In rats, circulating corticosterone and insulin are involved in regulation of the hypothalamic neuropeptide Y (NPY) system, which in turn, is involved in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Since the HPA axis and stress responsivity is altered in diseases such as depression, we investigated interactions between the effects of stress and antidepressant drug treatment on arcuate nucleus and locus coeruleus NPY mRNA expressions using in-situ hybridization histochemistry. After acute (2 h) and repeated immobilization (2 h daily, for 14 days), plasma concentrations of corticosterone increased, and those of insulin decreased. The expression of NPY mRNA was significantly increased in the arcuate nucleus, but was unchanged in the locus coeruleus following acute and repeated immobilization. Adrenalectomized rats with systemic corticosterone replacement (ADX+CORT), whose corticosterone concentration was maintained at approximately 50-100 ng/ml during repeated stress, showed a decrease in plasma insulin and an increase in arcuate nucleus NPY mRNA similar to that observed in sham rats, suggesting that changes in NPY mRNA levels are more closely tied to circulating insulin than to circulating corticosterone. In contrast, locus coeruleus NPY mRNA expressions in ADX+CORT rats were significantly higher than those in sham rats after repeated stress. Desmethylimipramine (DMI) treatment for 24 days did not affect basal plasma concentrations of corticosterone or insulin, or arcuate nucleus NPY mRNA expressions, but significantly decreased basal levels of locus coeruleus NPY mRNA compared to saline-treated rats. After repeated immobilization (2 h daily, for 4 days), DMI significantly reduced the stress-induced rise in locus coeruleus NPY mRNA levels, but potentiated the stress-induced rise in arcuate nucleus NPY mRNA expression. These results demonstrate that: (1) the increase in arcuate nucleus NPY mRNA expressions in stressed rats closely follows the decrease in plasma concentrations of insulin; (2) increases in NPY mRNA expressions occur in the absence of changes in plasma corticosterone; and (3) desipramine treatment potentiated the effect of stress on arcuate nucleus NPY mRNA expressions, but blocked the repeated stress-induced increase in locus coeruleus NPY mRNA expressions. Thus, NPY mRNA expression in the arcuate nucleus and the locus coeruleus is sensitive to the effects of stress and to the antidepressant drug desipramine, but the arcuate nucleus NPY system is regulated by different mechanisms than the locus coeruleus NPY system. The results provide further evidence for the importance of circulating insulin in the regulation of the arcuate nucleus NPY system.

Adrenalectomy↗

PubMed2000

In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer's disease: a central role for bound transition metals.

There is a great deal of evidence to support a pathogenic role of oxidative stress in Alzheimer's disease (AD), but the sources of reactive oxygen species have not been directly demonstrated. In this study, using a novel in situ detection system, we show that neurofibrillary tangles and senile plaques are major sites for catalytic redox reactivity. Pretreatment with deferoxamine or diethylenetriaminepentaacetic acid abolishes the ability of the lesions to catalyze the H2O2-dependent oxidation of 3,3'-diaminobenzidine (DAB), strongly suggesting the involvement of associated transition metal ions. Indeed, following chelated removal of metals, incubation with iron or copper salts reestablished lesion-dependent catalytic redox reactivity. Although DAB oxidation can also detect peroxidase activity, this was inactivated by H2O2 pretreatment before use of DAB, as shown by a specific peroxidase detection method. Model studies confirmed the ability of certain copper and iron coordination complexes to catalyze the H2O2-dependent oxidation of DAB. Also, the microtubule-associated protein tau, as an in vitro model for proteins relevant to AD pathology, was found capable of adventitious binding of copper and iron in a redox-competent manner. Our findings suggest that neurofibrillary tangles and senile plaques contain redox-active transition metals and may thereby exert prooxidant or possibly antioxidant activities, depending on the balance among cellular reductants and oxidants in the local microenvironment.

3,3'-Diaminobenzidine↗

PubMed2000

In Alzheimer's disease, heme oxygenase is coincident with Alz50, an epitope of tau induced by 4-hydroxy-2-nonenal modification.

In this study, we compared the neuronal induction of the antioxidant heme oxygenase-1 (HO-1) in Alzheimer's disease with abnormalities in tau marked by antibodies recognizing either phosphorylation (AT8) or conformational change (Alz50). The epitope recognized by Alz50 shows a complete overlap with HO-1-containing neurons, but AT8 recognized these neurons as well as neurons not displaying HO-1. These findings suggest that tau phosphorylation precedes the HO-1 response and that HO-1 is coincident with the Alz50 epitope. This led us to consider whether oxidative damage plays a role in forming the Alz50 epitope. We found that 4-hydroxy-2-nonenal (HNE), a highly reactive product of lipid peroxidation, reacts with normal tau and induces the Alz50 epitope in tau. It is important that the ability of HNE to create the Alz50 epitope not only is dependent on lysine residues of tau but also requires tau phosphorylation because neither methylated, recombinant, nor dephosphorylated tau reacts with HNE to create the Alz50 epitope. Supporting the in vivo relevance of this observation, endogenous paired helical filament-tau isolated from subjects with Alzheimer's disease was immunoreactive with an antibody to a stable HNE-lysine adduct, as were all vulnerable neurons in subjects with Alzheimer's disease but not in control individuals. Together, these findings support the involvement of oxidative damage early in neurofibrillary tangle formation in Alzheimer's disease and also suggest that HNE modification contributes to the generation of the tau conformation defining the Alz50 epitope. These findings provide evidence that an interplay between phosphorylation of tau and neuronal oxidative stress-induced pathology is important in the formation of neurofibrillary tangles.

Aged↗

PubMed2000

Metabolic, metallic, and mitotic sources of oxidative stress in Alzheimer disease.

Cell bodies of neurons at risk of death in Alzheimer disease (AD) have increased lipid peroxidation, nitration, free carbonyls, and nucleic acid oxidation. These oxidative changes are uniform among neurons and are seen whether or not the neurons display neurofibrillary tangles and, in fact, are actually reduced in the latter case. In consideration of this localization of damage, in this review, we provide a summary of recent work demonstrating some key abnormalities that may initiate and promote neuronal oxidative damage. First, mitochondrial abnormalities might be the source of reactive oxygen species yielding perikaryal oxidative damage. The common 5-kb deletion mitochondrial (mt)DNA subtype was greatly increased in the AD cases, but only in neurons at risk. The importance of such mitochondrial abnormalities to oxidative stress was indicated by a high correlation coefficient between the extent of the mtDNA increase and RNA oxidative damage (r2 = 0.87). Nonetheless, because mitochondria in AD do not show striking oxidative damage, as one would expect if they were the direct producer of free radical species, we suspected that abnormal mitochondria supply a key reactant that, once in the cytoplasm, releases radicals. One such reactant, hydrogen peroxide, (H2O2), abundant in mitochondria, can react with iron via the Fenton reaction to produce.OH. To demonstrate this directly using a modified cytochemical technique that relies on the formation of mixed valence iron complexes, we found that redox-active iron is associated with vulnerable neurons. Interestingly, removal of iron was completely affected by using deferroxamine, after which iron could be rebound to re-establish lesion-dependent catalytic redox reactivity. Characterization of the iron-binding site suggests that binding is dependent on available histidine residues and on protein conformation. Taken together with our previous studies showing abnormalities in the iron homeostatic system including heme oxygenase, iron regulatory proteins 1 and 2, ceruloplasmin, and dimethylargininase, our results indicate that iron misregulation could play an important role in the pathogenesis of AD and therefore chelation therapy may be a useful therapeutic approach. Finally, we wanted to determine the proximal cause of mitochondrial abnormalities. One interesting mechanisms involves re-entry into the cell cycle, at which point organellokinesis and proliferation results in increased mitochondria. Supporting this, we have considerable in vivo and in vitro evidence for mitotic disturbances in AD and its relationship with the pathogenesis of AD.

Alzheimer Disease↗

PubMed2000

Protein disulfide isomerase in Alzheimer disease.

There is a great deal of evidence that places oxidative stress as a proximal event in the natural history of Alzheimer disease (AD). In addition to increased damage, there are compensatory increases in the levels of free sulfhydryls, glucose-6-phosphate dehydrogenase, and NAD(P)H:quinone oxidoreductase 1. To investigate redox homeostasis further in AD, we analyzed protein disulfide isomerase (PDI), a multifunctional enzyme, which catalyzes the disruption and formation of disulfide bonds. PDI plays a pivotal role in both secreted and cell-surface-associated protein disulfide rearrangement. In this study, we show that PDI specifically localizes to neurons, where there is no substantial increase in AD compared to age-matched controls. These findings indicate that the neurons at risk of death in AD do not show a substantial change in PDI to compensate for the increased sulfhydryls and reductive state found during the disease. This suggests that, despite compensatory reductive changes in AD, the level of PDI is sufficiently high physiologically in neurons to accommodate a more reducing environment.

Adolescent↗

PubMed2000

Evidence for a novel heme-binding protein, HasAh, in Alzheimer disease.

Multiple lines of evidence indicate that oxidative stress is an integral component of the pathogenesis of Alzheimer disease (AD). The precipitating cause of such oxidative stress may be misregulated iron homeostasis because there are profound alterations in heme oxygenase-1 (HO-1), redox-active iron, and iron regulatory proteins. In this regard, HasA, a recently characterized bacterial protein involved in heme acquisition and iron metabolism, may also be important in the generation of reactive oxygen species (ROS) given its ability to bind heme and render iron available for free radical generation through the Fenton reaction. To study further the role of heme binding and iron metabolism in AD, we show an abnormal localization of anti-HasA to the neurofibrillary pathology of AD, but not in normal-appearing neurons in the brains of cases of AD or in age-matched controls. These results suggest the increased presence in AD of a HasA homologue or protein sharing a common epitope with HasA, which we term HasAh. We conclude that heme binding of HasAh is a potential source of free soluble iron and therefore toxic free radicals in AD and in aging. This furthers the evidence that redox-active iron and subsequent Fenton reaction generating reactive oxygen are critical factors in the pathogenesis of AD.

Aged↗

PubMed2000

Activation of p38 kinase links tau phosphorylation, oxidative stress, and cell cycle-related events in Alzheimer disease.

The temporal association between oxidative stress and the hallmark pathologies of Alzheimer disease (AD) demonstrates that oxidative stress is among the earliest events in the disease. Nonetheless, neither the consequences of oxidative stress nor how oxidative stress relates to other pathological features of the disease are clear at this point. To begin to address these issues, we investigated p38 kinase, which is induced by oxidative stress, in the pathogenesis of AD. In hippocampal and cortical brain regions of individuals with AD, p38 is exclusively localized in association with neurofibrillar pathology. By marked contrast, these brain regions exhibit a low level of diffuse p38 staining in the neuronal cytoplasm in controls. We found a complete overlap of the immunostaining profiles of p38 and tau-positive neurofibrillary pathology and that the majority of p38 was activated in AD neurons, both of which support an association of p38 with the disease process. Moreover, the finding that PHF-tau co-immunoprecipitates with p38, and that p38 co-purifies with PHF-tau, strongly suggests that they are physically associated in vivo. Since p38 is also implicated in cell cycle regulation, our findings provide a link between the cell cycle re-entrant phenotype, cytoskeletal phosphorylation and oxidative stress in AD.

Aged↗

PubMed2000

Neuronal oxidative stress precedes amyloid-beta deposition in Down syndrome.

The predictable chronological sequence of pathological events in Down syndrome (DS) provides the opportunity to rigorously investigate the relationship between oxidative stress and amyloid-beta (Abeta) deposition. In this study, we report a marked accumulation of oxidized nucleic acid, 8-hydroxyguanosine (8OHG), and oxidized protein, nitrotyrosine, in the cytoplasm of cerebral neurons in DS with the levels of nucleic acid and protein oxidation paralleling each other. Relative density measurements of neuronal 8OHG immunoreactivity showed that there was a significant increase (p < 0.02) in DS (n = 22, ages 0.3-65 yr) compared with age-matched controls (n = 10, ages 0.3-64 yr). As a function of age, 8OHG immunoreactivity increased significantly in the teens and twenties (p < 0.04), while Abeta burden only increased after age 30 (p < 0.0001). In 9 cases of DS bearing Abeta deposition, the extent of deposits of Abeta ending at amino acid 42 (Abeta42) was actually associated with a decrease in relative 8OHG (r = -0.79, p < 0.015) while Abeta40 was not. These findings suggest that in brains of patients with DS, increased levels of oxidative damage occur prior to the onset of Abeta deposition.

Adolescent↗

PubMed2000

Lipoperoxidation is selectively involved in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by extensive neurofibrillary tangle (NFT) formation and neuronal loss in selective neuronal populations. Currently, no clues to the biological events underlying the pathological process have emerged. In Alzheimer disease (AD), which shares with PSP the occurrence of NFTs, advanced glycation end products (AGEs) as well as oxidation adducts have been found to be increased in association with neurofibrillary pathology. The presence and the amount of lipid and protein oxidation markers, as well as of pyrraline and pentosidine. 2 major AGEs, was assessed by biochemical, immunochemical, and immunocytochemical analysis in midbrain tissue from 5 PSP cases, 6 sporadic AD cases, and 6 age-matched control cases. The levels of 4-hydroxynonenal (HNE) and thiobarbituric acid reactive substances (TBARS), 2 major products of lipid peroxidation, were significantly increased by 1.6-fold (p < 0.04) and 3.9-fold (p < 0.01), respectively, in PSP compared with control tissues, whereas in AD only TBARS were significantly increased. In PSP tissue the intensity of neuronal HNE immunoreactivity was proportional to the extent of abnormal aggregated tau protein. The amount of protein oxidation products and AGEs was instead similar in PSP and control tissues. In AD, a higher but not significant level of pyrraline and pentosidine was measured, whereas the level of carbonyl groups was doubled. These findings indicate that in PSP, unlike in AD, lipid peroxidation is selectively associated with NFT formation. The intraneuronal accumulation of toxic aldehydes may contribute to hamper tau degradation, leading to its aggregation in the PSP specific abnormal filaments.

Aged↗

PubMed2000

Oxidative stress, antioxidants, and Alzheimer disease.

Recent evidence in the field of Alzheimer disease research has highlighted the importance of oxidative processes in its pathogenesis. Examination of cellular changes shows that oxidative stress is an event that precedes the appearance of neurofibrillary tangles, one of the hallmark pathologies of the disease. Although it is still unclear what the initial source of the oxidative stress is in Alzheimer disease, it is likely that the process is highly dependent on the presence of redox-active transition metals, such as iron and copper. Because of the proximal role that oxidative stress mechanisms seem to play in the pathogenesis of Alzheimer disease, further investigation in this realm may lead to novel therapeutic strategies.

Alzheimer Disease↗

PubMed2000

Using structured implicit review to assess quality of care in the Program of All-Inclusive Care for the Elderly (PACE)

OBJECTIVE: To develop a quality assessment tool for care rendered to enrollees in the Program for All-inclusive Care of the Elderly (PACE) that can discriminate care quality ratings across PACE sites. DESIGN: Structured implicit review (SIR) of medical records by trained geriatricians and geriatric nurse practitioners. SETTING: Eight PACE sites. PARTICIPANTS: Older adults enrolled in a PACE program for at least 6 months (n = 313). MEASUREMENTS: Process and outcome measures for both overall care and 14 specific conditions (tracers) managed up to 1 year. RESULTS: Overall care quality was judged to be above a community standard in 56% and below standard in 8% of cases. Process of care was rated as very good or good in 70% of the cases. Outcomes depended on how questions were phrased: only 19% of cases improved, whereas 28% were judged to have fared better than expected given their condition at baseline. The SIR method produced ratings demonstrating considerable variability across the sites; three of the sites consistently showed poorer quality ratings than the other five. CONCLUSIONS: PACE care was generally assessed to be of good quality, but with room for improvement. Despite significant limitations of poor interrater reliability for process of care measures, excessive time involved for the reviews, and lack of a control group, the SIR method was able to consistently discriminate quality ratings among PACE sites. A modified version of the assessment instrument could prove useful in a quality improvement program for PACE care.

Aged↗

PubMed2000

Arson. Tracking the culprit in Alzheimer's disease.

By focusing on the lesions in Alzheimer's disease, and regarding them as either critical or irrelevant, researchers may have missed much regarding the origin and pathogenesis of this disease. In this article we consider that the lesions are so obvious not only because they are pathognomonic for Alzheimer's disease, but also because they represent a major departure from normal physiology. We suggest that these myriad pathological changes are homeostatic compensatory mechanisms to aging.

Aging↗

PubMed2000

Prospects for noninvasive imaging of brain amyloid beta in Alzheimer's disease.

The brain in patients with Alzheimer's disease (AD) contains large amounts of fibrillary amyloid beta protein. Studies attempting to use levels of amyloid beta protein in plasma, cerebrospinal fluid or skin as diagnostic tests for the disease have not been fruitful. A method for the noninvasive detection of cerebral amyloid beta would be valuable for dementia differential diagnosis, pathophysiology and monitoring of anti-amyloid therapies. Anti-amyloid monoclonal antibody 10H3 has been evaluated as an amyloid-imaging ligand, without success. Important considerations in the development of amyloid-imaging ligands include choice of radiolabel and physical and biological half-lives, route of administration, protein binding, use of control molecules, and imaging techniques. It is important that imaging studies be designed to reflect the slow nature of the process of amyloid deposition. We used a transgenic mouse model overexpressing beta protein precursor (beta PP) to assess the binding of basic fibroblast growth factor (bFGF) and serum amyloid P component (SAP) to amyloid beta (A beta) plaques in mouse brain. Although the binding of these ligands is similar to AD, neither is found endogenously associated with A beta deposits. Because SAP is a component of mouse serum, these findings suggest the blood-brain barrier in transgenic mice is not affected as it is in AD. These findings suggest that the transgenic mouse may be used as a model for evaluation of A beta imaging methods.

Alzheimer Disease↗

PubMed2000

Study of choice between accident and emergency departments and general practice centres for out of hours primary care problems.

OBJECTIVES: To determine the reasons for choosing between primary care out of hours centres and accident and emergency (A&E) departments for patients with primary care problems. METHODS: Interviews using a semistructured approach of samples of patients attending A&E departments and general practitioner (GP) out of hours centres for primary care problems. RESULTS: 102 patient interviews were undertaken. Sixty two per cent of A&E attenders were unemployed compared with 41% of out of hours attenders. White people were more likely to attend A&E departments and Asians the out of hours centre (p<0.01) and unemployed were more likely to attend A&E departments (70% v 30%). Some 46.3% of A&E department attenders had not contacted their GP before attending; 81.3% of first time users of the out of hours centre found out about it on the day of interview. Those attending A&E thought waiting times at the out of hours centre would be 6.3 hours (median) compared with a median perceived time of 2.9 hours by those actually attending the out of hours centre. Actual time was actually much less. CONCLUSION: Once patients have used the GP out of hours centre they are more likely to use it again. Education should be targeted at young adults, the unemployed and white people. Patients should be encouraged to contact their GP before A&E department attendance for non-life threatening conditions. Waiting time perception may be an important reason for choice of service.

Adult↗

PubMed2000

Evaluation of (18)fluorodeoxyglucose positron emission tomography ((18)FDG PET) in the detection of malignant peripheral nerve sheath tumours arising from within plexiform neurofibromas in neurofibromatosis 1.

OBJECTIVES: The ability of (18)fluorodeoxyglucose positron emission tomography ((18)FDG PET) to detect malignant change in plexiform neurofibromas from patients with neurofibromatosis 1 (NF1) was evaluated. METHODS: Eighteen NF1 patients who presented with pain, increase in size, or neurological deficit associated with a plexiform neurofibroma were assessed. Magnetic resonance imaging determined the site and extent of the lesion. Qualitative(18)FDG PET was performed and the standard uptake value (SUV) measured the regional glucose metabolism. Histological confirmation of the diagnosis was obtained in 10 patients. RESULTS: Twenty three plexiform neurofibromas were detected in 18 patients. Seven malignant peripheral nerve sheath tumours, four high grade and three low grade tumours, occurred in five patients. In one patient the clinical and radiological characteristics of the tumour suggested malignancy, but histology was inconclusive. Fifteen benign plexiform neurofibromas were identified in 12 patients and these findings were confirmed histologically in five lesions from four patients. Ten plexiform neurofibromas occurring in eight patients were considered benign on(18)FDG PET and the patients did not undergo surgery. They remained stable or their symptoms improved on clinical follow up (median 9 months). The results of qualitative (18)FDG PET were interpreted as indicating that 13 plexiform neurofibromas were benign and 10 were malignant. No malignant tumours were classified as benign, but two benign tumours were reported as malignant. The SUV was calculated for 20 tumours and was significantly higher in five malignant tumours 5.4 (SD 2.4), than in 15 benign tumours 1.54 (SD 0.7), p=0.002. There was an overlap between benign and malignant tumours in the SUV range 2.7-3.3. CONCLUSIONS: (18)FDG PET is helpful in determining malignant change in plexiform neurofibromas in NF1. Increased separation between benign and malignant lesions could be obtained by calculating the SUV at about 200 minutes after injection of (18)FDG, when the peak activity concentration is obtained in malignant tumours.

Adolescent↗

PubMed2000

Stress-induced alterations in corticotropin-releasing hormone and vasopressin gene expression in the paraventricular nucleus during ontogeny.

From postnatal day (PND) 4 to 14, neonates display a minimal pituitary-adrenal response to mild stress, the so-called 'stress hyporesponsive period' (SHRP). During the SHRP, maternal deprivation (MD) alters the pituitary-adrenal system, enabling neonates to become endocrine responsive to specific stimuli. We have previously reported that during the SHRP, mild stress enhances corticotropin-releasing hormone (CRH) messenger RNA (mRNA) expression in the paraventricular nucleus (PVN). Insofar as elevated CRH mRNA was observed both in the presence and absence of adrenocorticotropin (ACTH) release, we hypothesized that other ACTH secretagogues may participate in the pituitary stress response. During the SHRP, does arginine vasopressin (AVP) complement the actions of CRH which might be reflected centrally by the enhanced biosynthesis of both neuropeptides? To test this hypothesis we examined the time course of stress-induced CRH and AVP mRNA in the PVN at PND 6, 12, and 18. As an index of neural activity, c-fos mRNA in the PVN was also examined. Restraint was used as the stressor and MD was employed to enable an endocrine response during the SHRP. Despite the absence of stress-induced ACTH, in nondeprived pups during the SHRP, CRH mRNA was rapidly enhanced. In their maternally deprived (DEP) counterparts, ACTH levels were increased, and a significant induction of CRH mRNA was only observed at day 12. AVP mRNA levels were elevated in DEP 12-day-old pups at 15, 30 and 60 min. In rats beyond the SHRP, plasma ACTH levels, CRH and AVP mRNA were all enhanced following restraint. At PND 18, elevated CRH mRNA was not observed until 4 h after stimulus. Following restraint, c-fos mRNA was increased at all three ages, although the magnitude of c-fos response was less during the SHRP. These results demonstrate that when restraint elicits prototypical ACTH release, the neonatal central response is to enhance the biosynthesis of both AVP and CRH. If nucleic acid changes correlate with release, the increased synthesis of both neuropeptides may indicate the potential for AVP to synergize with CRH during the neonatal stress response.

Adrenocorticotropic Hormone↗