Ralf Nass - Academia.edu (original) (raw)

Papers by Ralf Nass

The Journal of Clinical Endocrinology & Metabolism, 1993

It is widely believed that benign prostatic hyperplasia (BPH) is associated with aging. Thus, the... more It is widely believed that benign prostatic hyperplasia (BPH) is associated with aging. Thus, the question arises whether or not a correlation exists between the well known prostatic androgen and

The Journal of Clinical Endocrinology Metabolism, Jul 2, 2013

Context: Ghrelin, an acylated peptide hormone secreted from the gut, regulates appetite and metab... more Context: Ghrelin, an acylated peptide hormone secreted from the gut, regulates appetite and metabolism. Elucidating its pattern of secretion in the fed and fasted states is important in the face of the obesity epidemic.

Obesity and Metabolism, 2009

Detailed assessment of physiological and pathophysiological GH secretion has, until recently, bee... more Detailed assessment of physiological and pathophysiological GH secretion has, until recently, been limited by the poor sensitivity of the available assays. We have used an ultrasensitive chemiluminescence GH assay (sensitivity, 0.002 g/L) to study 24-h GH profiles (20-min sampling) from 24 patients who had been treated for hypothalamicpituitary disease with surgery and irradiation and from 24 healthy control subjects matched for age, sex, and body mass index.

Endocrinology, Jul 1, 2000

Synthetic GH secretagogues (GHSs) act via a receptor (GHS-R) distinct from that of GH-releasing h... more Synthetic GH secretagogues (GHSs) act via a receptor (GHS-R) distinct from that of GH-releasing hormone. The GHS-R has been cloned from the pituitary and is expressed not only in the pituitary but also in specific areas of the brain, including the hypothalamus. Recent studies suggest that hypothalamic GHS-R expression is regulated by GH. This study was designed to investigate whether pituitary GHS-R expression is modulated by GH. Female Wistar-Furth rats were injected sc with either saline (control) or GC tumor cells (GC) that secrete rat GH. The tumors were allowed to develop for 1-4 weeks. At weeks 1-4, control (n ϭ 4 -8) and GC rats (n ϭ 3-8) were killed. Pituitary GHS-R messenger RNA (mRNA) was measured by a quan-titative competitive PCR assay. The endogenous GHS-R mRNA levels were measured by determining the amount of competitive template RNA required to produce equimolar amounts of native and competitive template PCR products. The mean log plasma GH levels were significantly greater in the GC rat group than in the control group at weeks 2, 3, and 4. At these times, the mean log pituitary GHS-R mRNA contents were significantly lower in the GC rat group than in the control group. No relationship could be established between log estradiol levels and GHS-R levels. These data indicate that pituitary GHS-R expression is modulated by GH.

Annals of Internal Medicine, Nov 4, 2008

BackgroundGrowth hormone (GH) secretion and muscle mass decline from mid-puberty throughout life ... more BackgroundGrowth hormone (GH) secretion and muscle mass decline from mid-puberty throughout life culminating in sarcopenia, frailty, decreased function and loss of independence.ObjectiveDetermine if an oral ghrelin mimetic (MK-677) would enhance GH secretion into the young adult range without serious adverse effects, prevent the decline of fat-free mass (FFM), and decrease abdominal visceral fat (AVF) in healthy older adults.DesignTwo-year, double-blind, randomized, placebo-controlled, modified-crossover clinical trial.SettingGeneral Clinical Research Center study performed at a University Hospital.ParticipantsSixty-five healthy men and women (on or off hormone replacement therapy) ages 60-81.InterventionOral administration of MK-677 (25 mg) or placebo once daily.MeasurementsGrowth hormone and insulin-like growth factor-I (IGF-I); FFM and AVF were the primary endpoints after one year of treatment. Other endpoints: weight, fat mass, insulin sensitivity, lipid and cortisol levels, bone mineral density, limb lean and fat mass, isokinetic strength, function and quality of life; all endpoints were assessed at baseline and every 6 months.LimitationsStudy design (duration and subject number) not sufficient to evaluate functional endpoints in healthy elderlyResultsDaily MK-677 significantly increased GH and IGF-I levels to those of healthy young adults without serious adverse effects. With placebo, mean (95% Cl) FFM decreased -0.5 (-1.1 to 0.2) kg, however, FFM increased 1.1 (0.7 to 1.5) kg with MK-677 (P<0.001, MK-677 vs. placebo); body cell mass as reflected by intracellular water decreased -1.0 (-2.1 to 0.2) kg with placebo, but increased 0.8 (-0.1 to 1.6) kg with MK-677 (P=0.021). There were no significant differences in AVF or total fat mass. However, the average increase in limb fat in the MK-677 group (1.1 kg) was greater than with placebo (0.24 kg); P=0.001. Body weight increased 0.8 (-0.3 to 1.8) kg with placebo and 2.7 (2.0 to 3.5) kg with MK-677 (P=0.003). Fasting blood glucose increased an average of 0.3 mmol/L (5 mg/dL) with MK-677 (P=0.015) and insulin sensitivity declined. The most frequent side effects were an increase in appetite that subsided within a few months and transient, mild lower extremity edema and muscle pain. Low density lipoprotein cholesterol decreased -0.14 (-0.27 to -0.01) mmol/L [-5.4 (-10.4 to -0.4) mg/dL] with MK-677 (P=0.026); there were no differences in total or high density lipoprotein cholesterol. Cortisol increased 47 (28 to 71) nmol/L [1.7 (1.0 to 2.6 µg/dL)] with MK-677 (P=0.020). Changes in bone mineral density consistent with increased bone remodeling occurred in MK-677-treated subjects. Increased FFM did not result in changes in strength or function. Two-year exploratory analyses confirmed the 1-year results.ConclusionsThe ghrelin mimetic MK-677 enhanced pulsatile GH secretion and significantly increased FFM over 12 months and was generally well tolerated. Long-term functional, and ultimately pharmaco-economic, studies in elderly adults are indicated.

GH has diverse biological actions that are mediated by binding to a specific, high-affinity cell ... more GH has diverse biological actions that are mediated by binding to a specific, high-affinity cell surface receptor (GHR). Expression of GHR is tissue specific and a requirement for cellular responsiveness to GH. IGF-I is produced in multiple tissues and regulated in part by GH through GHR. In this study, we evaluated GHR and IGF-I mRNA expression in pituitary gland and compared the levels with those derived from liver of bovine GH transgenic, GH antagonist transgenic, lit/lit mice, and their respective controls using real-time RT-PCR. In liver, both GHR and IGF-I mRNA expressions were regulated in parallel with GH action in all three animal models, and there was a strong correlation between GHR and IGF-I mRNA levels. In the pituitary gland, increased expression of IGF-I mRNA in the pituitary of bovine GH transgenic mice was observed, whereas IGF-I expression in GH antagonist transgenic or lit/lit mice was similar to that observed in control animals. There were no differences of GHR mRNA levels in pituitary gland of any groups we examined. There was also no correlation between GHR and IGF-I mRNA levels in any group in the pituitary gland. In conclusion, we found that hepatic GHR and IGF-I mRNA levels were strongly correlated with each other in chronic GH excess or deficient state, and that regulation and correlation between local GHR and IGF-I mRNA levels induced by GH is different between liver and pituitary gland. Abbreviations: bGH, Bovine transgenic GH; GHA, GH antagonist transgenic; GHR, GH receptor; MT, metallothionein I.

Ghrelin in Health and Disease, 2012

ABSTRACT Frailty is one of the key features of aging and it is associated with a loss of function... more ABSTRACT Frailty is one of the key features of aging and it is associated with a loss of function, an increased risk of falls, and ultimately loss of the ability to live independently. Based on the demographic shift of the older population, as a result of the aging of the baby boomers, interventions to slow or delay the development of frailty will be of increasing importance. One of the physiologic correlates of frailty is the cachexia of aging. The underlying mechanism of the cachexia of aging is cytokine-associated wasting of protein and energy stores and ghrelin receptor agonists target some of these mechanisms. Clinical trials have shown that ghrelin receptor agonists have orexigenic effects, enhance GH secretion, and increase lean body mass and limb fat mass in the elderly. The potential benefits of ghrelin receptor agonists in the treatment of cachexia of aging and of cachexia secondary to various diseases are reviewed.

Annals of internal medicine

Background-Growth hormone (GH) secretion and muscle mass decline from mid-puberty throughout life... more Background-Growth hormone (GH) secretion and muscle mass decline from mid-puberty throughout life culminating in sarcopenia, frailty, decreased function and loss of independence.

The Journal of Clinical Endocrinology & Metabolism, 2015

Background: Acyl-ghrelin is a 28-amino acid peptide released from the stomach. Ghrelin O-acyl tra... more Background: Acyl-ghrelin is a 28-amino acid peptide released from the stomach. Ghrelin O-acyl transferase (GOAT) attaches an 8-carbon medium chain fatty acid (MCFA) (octanoate) to serine 3 of ghrelin. This acylation is necessary for ghrelin's activity. Animal data suggest that MCFAs provide substrate for GOAT and increase of nutritional octanoate increases acyl-ghrelin.

The Journal of clinical endocrinology and metabolism, 2014

Ghrelin is a 28-amino acid peptide released from the stomach. Ghrelin is found in the circulation... more Ghrelin is a 28-amino acid peptide released from the stomach. Ghrelin is found in the circulation in two forms: acyl- and desacyl-ghrelin. Acyl- and desacyl-ghrelin concentrations increase at night, when cortisol concentrations are low. Acute ghrelin administration increases ACTH and cortisol concentrations and a feedback loop between the ghrelin and ACTH-cortisol axis has been postulated. A previous study showed that exogenously induced hypercortisolism for 5 days decreased plasma ghrelin concentrations. The objective of the study was to determine whether a 4-hour infusion of hydrocortisone given at a time of low endogenous cortisol concentrations (11:00 pm to 3:00 am) acutely suppresses acyl- and desacyl-ghrelin. Eight healthy young men aged (mean ± SD) 21.5 ± 2.7 years with a body mass index of 22.4 ± 2.5 kg/m(2) were studied in a single-blind, placebo-controlled study during two separate overnight admissions on the Clinical Research Unit. The volunteers received either a 4-hour ...

Pediatric endocrinology reviews : PER, 2007

During the last 50 years a 20-year increase in the average life span was observed, and the averag... more During the last 50 years a 20-year increase in the average life span was observed, and the average life span worldwide is expected to increase by another 10 years by 2050 (1). Enhancing "healthy aging" and thus extending the time that the elderly are able to maintain their independence is a high priority. One of the major causes of dysfunction and disability in the elderly is loss of muscle mass and muscle strength - sarcopenia. We will review some of the aspects of sarcopenia in the elderly and arguments in favor and against GH replacement in the elderly. Since the study of Rudman and colleagues (2) was published there has been great interest in the role of the decline of growth hormone secretion observed during aging. The rationale and the basis for the hypothesis will be described and then we will discuss the results of clinical studies which to date have not demonstrated a clear clinical benefit of growth hormone replacement in normal aging subjects.

This report provides the results of an engineering study that evaluated the available technologie... more This report provides the results of an engineering study that evaluated the available technologies for stabilizing the plutonium stored at the Plutonium Finishing Plant located at the hanford Site in southeastern Washington. Further processing of the plutonium may be required to prepare the plutonium for interim (&amp;amp;amp;amp;amp;amp;lt;50 years) storage. Specifically this document provides the current plutonium inventory and characterization, the

Methods in Enzymology, 2009

This work presents a new approach to the analysis of aperiodic pulsatile heteroscedastic time-ser... more This work presents a new approach to the analysis of aperiodic pulsatile heteroscedastic time-series data, specifically hormone pulsatility. We have utilized growth hormone (GH) concentration timeseries data as an example for the utilization of this new algorithm. While many previously published approaches used for the analysis of GH pulsatility are both subjective and cumbersome to use, AutoDecon is a nonsubjective, standardized, and completely automated algorithm. We have employed computer simulations to evaluate the true-positive, the false-positive, the false-negative, and the sensitivity percentages of several of the routinely employed algorithms when applied to GH concentration time-series data. Based on these simulations, it was concluded that this new algorithm provides a substantial improvement over the previous methods. This novel method has many direct applications in addition to hormone pulsatility, for example, to time-domain fluorescence lifetime measurements, as the mathematical forms that describe these experimental systems are both convolution integrals.

The Prostate, 1989

Little is known about the cell kinetics on which development of benign prostatic hyperplasia is b... more Little is known about the cell kinetics on which development of benign prostatic hyperplasia is based. This prompted us to study the superoxide dismutase (SOD) activity, which is known 1) to correlate with the life span of cells and 2) to decrease with advancing age of cells. Therefore, SOD was measured in epithelium and stroma of the human prostate from patients of various ages (20-86 years) and compared with the activity in the postmitotic skeletal muscle. It was found that the highest mean specific SOD activity is present in skeletal muscle (4.0 mU.mg protein-1), followed by the stroma (2.1 mU.mg protein-1) and epithelium (1.4 mU.mg protein-1). Similar results were obtained when SOD activity was expressed per DNA (5.03, 1.73, and 0.16 mU.micrograms DNA-1, respectively). Comparing the slope of the age-dependent regression lines, it was demonstrated that the slope of the stroma is much closer to the slope of the postmitotic skeletal muscle than the slope of the epithelium. From the data, it was calculated that the average life span of stromal cells is probably longer than 30 years and of epithelial cells longer than 2 years. Hence in human prostatic tissue the average cell death rate might be rather low.

Proceedings of the National Academy of Sciences, 2010

Neuroendocrinology, 2004

Ghrelin and the synthetic growth hormone secretagogues (GHSs) activate a G-protein-coupled recept... more Ghrelin and the synthetic growth hormone secretagogues (GHSs) activate a G-protein-coupled receptor (GHS-R) originally cloned from the pituitary, but which is also expressed in the hypothalamus, in other areas of the brain and in numerous peripheral tissues. Several studies have shown that growth hormone (GH)-releasing hormone (GHRH) is necessary for GHSs to exert maximal GH release in vivo. The exact mechanism of this synergism is not clear. Previous data suggest that GHSs can affect pituitary GHS-R mRNA expression; however, it is unknown whether this effect is age dependent and whether hypothalamic GHS-Rs are also affected. In this study, we tested whether (a) the synthetic GHS hexarelin regulates mRNA expression of its own receptor at the pituitary and/or hypothalamus and whether this effect is age dependent, and (b) whether short-term treatment with GHRH or, conversely, passive immunization against GHRH affects pituitary GHS-R1a mRNA expression in infant (10 days old) and young adult rats. GHS-R1a mRNA expression was measured with competitive reverse transcriptase-polymerase chain reaction. Hexarelin treatment significantly increased pituitary and hypothalamic GHS-R1a mRNA levels in normal infant rats, but not in normal young adult rats. In addition, hexarelin administration also stimulated pituitary GHS-R1a mRNA in infant as well as in young adult rats passively immunized against GHRH. GHRH treatment significantly enhanced pituitary GHS-R1a mRNA expression in GHRH-deprived young adult rats, though it did not affect the basal levels of GHS-R1a mRNA in normal infant and adult rats. These data further support the hypothesis that GHRH can affect GHS-R1a expression and that hexarelin upregulates the expression of its own receptor at the pituitary as well as the hypothalamus in an age-dependent fashion.

Molecular and Cellular Endocrinology, 2011

Ghrelin, the natural ligand for the growth hormone (GH)-secretagogue receptor (GHS-R), is produce... more Ghrelin, the natural ligand for the growth hormone (GH)-secretagogue receptor (GHS-R), is produced predominantly in the stomach. It is present in the circulation in two major forms, an acylated and an unacylated form, both of which have reported activities. Some of the best understood main effects of acylated ghrelin administration include anorexic effects, increased appetite and the stimulation of GH secretion. Ghrelin also seems to plays a role in glucose homeostasis, lipid metabolism and immune function. Based on its orexigenic and metabolic effects, ghrelin and ghrelin mimetics have potential benefit in antagonizing protein breakdown and weight loss in catabolic conditions such as cancer cachexia, renal, cardiac and pulmonary disease, and age-related frailty. Ghrelin also has potentially useful positive effects on cardiac function and gastric motility. Ghrelin antagonists may be of benefit to increase insulin sensitivity and potentiate weight loss. The following chapter presents some background on ghrelin and ghrelin assays and discusses some of the potential therapeutic approaches for the use of ghrelin, ghrelin mimetic compounds and ghrelin antagonists in clinical disease.

Molecular and Cellular Endocrinology, 2011

In humans, growth hormone (GH) is secreted from the anterior pituitary in a pulsatile pattern. Th... more In humans, growth hormone (GH) is secreted from the anterior pituitary in a pulsatile pattern. The traditional view is that this secretory pattern is driven by two counter regulatory neurohormones, GHRH and somatostatin. Ghrelin, the natural ligand for the growth hormone (GH)-secretagogue receptor (GHS-R), is produced in the stomach. Ghrelin is the strongest GH secretagogue known to date, but the role of endogenous ghrelin in the regulation of circulating GH levels remains controversial. The following review examines the evidence suggesting that endogenous ghrelin may be a key regulator of GH peak amplitude and discusses studies of diseases with altered GH levels, where it is found that in these states GH and ghrelin levels change in a similar way.

The Journal of Clinical Endocrinology & Metabolism, 1993

It is widely believed that benign prostatic hyperplasia (BPH) is associated with aging. Thus, the... more It is widely believed that benign prostatic hyperplasia (BPH) is associated with aging. Thus, the question arises whether or not a correlation exists between the well known prostatic androgen and

The Journal of Clinical Endocrinology Metabolism, Jul 2, 2013

Context: Ghrelin, an acylated peptide hormone secreted from the gut, regulates appetite and metab... more Context: Ghrelin, an acylated peptide hormone secreted from the gut, regulates appetite and metabolism. Elucidating its pattern of secretion in the fed and fasted states is important in the face of the obesity epidemic.

Obesity and Metabolism, 2009

Detailed assessment of physiological and pathophysiological GH secretion has, until recently, bee... more Detailed assessment of physiological and pathophysiological GH secretion has, until recently, been limited by the poor sensitivity of the available assays. We have used an ultrasensitive chemiluminescence GH assay (sensitivity, 0.002 g/L) to study 24-h GH profiles (20-min sampling) from 24 patients who had been treated for hypothalamicpituitary disease with surgery and irradiation and from 24 healthy control subjects matched for age, sex, and body mass index.

Endocrinology, Jul 1, 2000

Synthetic GH secretagogues (GHSs) act via a receptor (GHS-R) distinct from that of GH-releasing h... more Synthetic GH secretagogues (GHSs) act via a receptor (GHS-R) distinct from that of GH-releasing hormone. The GHS-R has been cloned from the pituitary and is expressed not only in the pituitary but also in specific areas of the brain, including the hypothalamus. Recent studies suggest that hypothalamic GHS-R expression is regulated by GH. This study was designed to investigate whether pituitary GHS-R expression is modulated by GH. Female Wistar-Furth rats were injected sc with either saline (control) or GC tumor cells (GC) that secrete rat GH. The tumors were allowed to develop for 1-4 weeks. At weeks 1-4, control (n ϭ 4 -8) and GC rats (n ϭ 3-8) were killed. Pituitary GHS-R messenger RNA (mRNA) was measured by a quan-titative competitive PCR assay. The endogenous GHS-R mRNA levels were measured by determining the amount of competitive template RNA required to produce equimolar amounts of native and competitive template PCR products. The mean log plasma GH levels were significantly greater in the GC rat group than in the control group at weeks 2, 3, and 4. At these times, the mean log pituitary GHS-R mRNA contents were significantly lower in the GC rat group than in the control group. No relationship could be established between log estradiol levels and GHS-R levels. These data indicate that pituitary GHS-R expression is modulated by GH.

Annals of Internal Medicine, Nov 4, 2008

BackgroundGrowth hormone (GH) secretion and muscle mass decline from mid-puberty throughout life ... more BackgroundGrowth hormone (GH) secretion and muscle mass decline from mid-puberty throughout life culminating in sarcopenia, frailty, decreased function and loss of independence.ObjectiveDetermine if an oral ghrelin mimetic (MK-677) would enhance GH secretion into the young adult range without serious adverse effects, prevent the decline of fat-free mass (FFM), and decrease abdominal visceral fat (AVF) in healthy older adults.DesignTwo-year, double-blind, randomized, placebo-controlled, modified-crossover clinical trial.SettingGeneral Clinical Research Center study performed at a University Hospital.ParticipantsSixty-five healthy men and women (on or off hormone replacement therapy) ages 60-81.InterventionOral administration of MK-677 (25 mg) or placebo once daily.MeasurementsGrowth hormone and insulin-like growth factor-I (IGF-I); FFM and AVF were the primary endpoints after one year of treatment. Other endpoints: weight, fat mass, insulin sensitivity, lipid and cortisol levels, bone mineral density, limb lean and fat mass, isokinetic strength, function and quality of life; all endpoints were assessed at baseline and every 6 months.LimitationsStudy design (duration and subject number) not sufficient to evaluate functional endpoints in healthy elderlyResultsDaily MK-677 significantly increased GH and IGF-I levels to those of healthy young adults without serious adverse effects. With placebo, mean (95% Cl) FFM decreased -0.5 (-1.1 to 0.2) kg, however, FFM increased 1.1 (0.7 to 1.5) kg with MK-677 (P<0.001, MK-677 vs. placebo); body cell mass as reflected by intracellular water decreased -1.0 (-2.1 to 0.2) kg with placebo, but increased 0.8 (-0.1 to 1.6) kg with MK-677 (P=0.021). There were no significant differences in AVF or total fat mass. However, the average increase in limb fat in the MK-677 group (1.1 kg) was greater than with placebo (0.24 kg); P=0.001. Body weight increased 0.8 (-0.3 to 1.8) kg with placebo and 2.7 (2.0 to 3.5) kg with MK-677 (P=0.003). Fasting blood glucose increased an average of 0.3 mmol/L (5 mg/dL) with MK-677 (P=0.015) and insulin sensitivity declined. The most frequent side effects were an increase in appetite that subsided within a few months and transient, mild lower extremity edema and muscle pain. Low density lipoprotein cholesterol decreased -0.14 (-0.27 to -0.01) mmol/L [-5.4 (-10.4 to -0.4) mg/dL] with MK-677 (P=0.026); there were no differences in total or high density lipoprotein cholesterol. Cortisol increased 47 (28 to 71) nmol/L [1.7 (1.0 to 2.6 µg/dL)] with MK-677 (P=0.020). Changes in bone mineral density consistent with increased bone remodeling occurred in MK-677-treated subjects. Increased FFM did not result in changes in strength or function. Two-year exploratory analyses confirmed the 1-year results.ConclusionsThe ghrelin mimetic MK-677 enhanced pulsatile GH secretion and significantly increased FFM over 12 months and was generally well tolerated. Long-term functional, and ultimately pharmaco-economic, studies in elderly adults are indicated.

GH has diverse biological actions that are mediated by binding to a specific, high-affinity cell ... more GH has diverse biological actions that are mediated by binding to a specific, high-affinity cell surface receptor (GHR). Expression of GHR is tissue specific and a requirement for cellular responsiveness to GH. IGF-I is produced in multiple tissues and regulated in part by GH through GHR. In this study, we evaluated GHR and IGF-I mRNA expression in pituitary gland and compared the levels with those derived from liver of bovine GH transgenic, GH antagonist transgenic, lit/lit mice, and their respective controls using real-time RT-PCR. In liver, both GHR and IGF-I mRNA expressions were regulated in parallel with GH action in all three animal models, and there was a strong correlation between GHR and IGF-I mRNA levels. In the pituitary gland, increased expression of IGF-I mRNA in the pituitary of bovine GH transgenic mice was observed, whereas IGF-I expression in GH antagonist transgenic or lit/lit mice was similar to that observed in control animals. There were no differences of GHR mRNA levels in pituitary gland of any groups we examined. There was also no correlation between GHR and IGF-I mRNA levels in any group in the pituitary gland. In conclusion, we found that hepatic GHR and IGF-I mRNA levels were strongly correlated with each other in chronic GH excess or deficient state, and that regulation and correlation between local GHR and IGF-I mRNA levels induced by GH is different between liver and pituitary gland. Abbreviations: bGH, Bovine transgenic GH; GHA, GH antagonist transgenic; GHR, GH receptor; MT, metallothionein I.

Ghrelin in Health and Disease, 2012

ABSTRACT Frailty is one of the key features of aging and it is associated with a loss of function... more ABSTRACT Frailty is one of the key features of aging and it is associated with a loss of function, an increased risk of falls, and ultimately loss of the ability to live independently. Based on the demographic shift of the older population, as a result of the aging of the baby boomers, interventions to slow or delay the development of frailty will be of increasing importance. One of the physiologic correlates of frailty is the cachexia of aging. The underlying mechanism of the cachexia of aging is cytokine-associated wasting of protein and energy stores and ghrelin receptor agonists target some of these mechanisms. Clinical trials have shown that ghrelin receptor agonists have orexigenic effects, enhance GH secretion, and increase lean body mass and limb fat mass in the elderly. The potential benefits of ghrelin receptor agonists in the treatment of cachexia of aging and of cachexia secondary to various diseases are reviewed.

Annals of internal medicine

Background-Growth hormone (GH) secretion and muscle mass decline from mid-puberty throughout life... more Background-Growth hormone (GH) secretion and muscle mass decline from mid-puberty throughout life culminating in sarcopenia, frailty, decreased function and loss of independence.

The Journal of Clinical Endocrinology & Metabolism, 2015

Background: Acyl-ghrelin is a 28-amino acid peptide released from the stomach. Ghrelin O-acyl tra... more Background: Acyl-ghrelin is a 28-amino acid peptide released from the stomach. Ghrelin O-acyl transferase (GOAT) attaches an 8-carbon medium chain fatty acid (MCFA) (octanoate) to serine 3 of ghrelin. This acylation is necessary for ghrelin's activity. Animal data suggest that MCFAs provide substrate for GOAT and increase of nutritional octanoate increases acyl-ghrelin.

The Journal of clinical endocrinology and metabolism, 2014

Ghrelin is a 28-amino acid peptide released from the stomach. Ghrelin is found in the circulation... more Ghrelin is a 28-amino acid peptide released from the stomach. Ghrelin is found in the circulation in two forms: acyl- and desacyl-ghrelin. Acyl- and desacyl-ghrelin concentrations increase at night, when cortisol concentrations are low. Acute ghrelin administration increases ACTH and cortisol concentrations and a feedback loop between the ghrelin and ACTH-cortisol axis has been postulated. A previous study showed that exogenously induced hypercortisolism for 5 days decreased plasma ghrelin concentrations. The objective of the study was to determine whether a 4-hour infusion of hydrocortisone given at a time of low endogenous cortisol concentrations (11:00 pm to 3:00 am) acutely suppresses acyl- and desacyl-ghrelin. Eight healthy young men aged (mean ± SD) 21.5 ± 2.7 years with a body mass index of 22.4 ± 2.5 kg/m(2) were studied in a single-blind, placebo-controlled study during two separate overnight admissions on the Clinical Research Unit. The volunteers received either a 4-hour ...

Pediatric endocrinology reviews : PER, 2007

During the last 50 years a 20-year increase in the average life span was observed, and the averag... more During the last 50 years a 20-year increase in the average life span was observed, and the average life span worldwide is expected to increase by another 10 years by 2050 (1). Enhancing "healthy aging" and thus extending the time that the elderly are able to maintain their independence is a high priority. One of the major causes of dysfunction and disability in the elderly is loss of muscle mass and muscle strength - sarcopenia. We will review some of the aspects of sarcopenia in the elderly and arguments in favor and against GH replacement in the elderly. Since the study of Rudman and colleagues (2) was published there has been great interest in the role of the decline of growth hormone secretion observed during aging. The rationale and the basis for the hypothesis will be described and then we will discuss the results of clinical studies which to date have not demonstrated a clear clinical benefit of growth hormone replacement in normal aging subjects.

This report provides the results of an engineering study that evaluated the available technologie... more This report provides the results of an engineering study that evaluated the available technologies for stabilizing the plutonium stored at the Plutonium Finishing Plant located at the hanford Site in southeastern Washington. Further processing of the plutonium may be required to prepare the plutonium for interim (&amp;amp;amp;amp;amp;amp;lt;50 years) storage. Specifically this document provides the current plutonium inventory and characterization, the

Methods in Enzymology, 2009

This work presents a new approach to the analysis of aperiodic pulsatile heteroscedastic time-ser... more This work presents a new approach to the analysis of aperiodic pulsatile heteroscedastic time-series data, specifically hormone pulsatility. We have utilized growth hormone (GH) concentration timeseries data as an example for the utilization of this new algorithm. While many previously published approaches used for the analysis of GH pulsatility are both subjective and cumbersome to use, AutoDecon is a nonsubjective, standardized, and completely automated algorithm. We have employed computer simulations to evaluate the true-positive, the false-positive, the false-negative, and the sensitivity percentages of several of the routinely employed algorithms when applied to GH concentration time-series data. Based on these simulations, it was concluded that this new algorithm provides a substantial improvement over the previous methods. This novel method has many direct applications in addition to hormone pulsatility, for example, to time-domain fluorescence lifetime measurements, as the mathematical forms that describe these experimental systems are both convolution integrals.

The Prostate, 1989

Little is known about the cell kinetics on which development of benign prostatic hyperplasia is b... more Little is known about the cell kinetics on which development of benign prostatic hyperplasia is based. This prompted us to study the superoxide dismutase (SOD) activity, which is known 1) to correlate with the life span of cells and 2) to decrease with advancing age of cells. Therefore, SOD was measured in epithelium and stroma of the human prostate from patients of various ages (20-86 years) and compared with the activity in the postmitotic skeletal muscle. It was found that the highest mean specific SOD activity is present in skeletal muscle (4.0 mU.mg protein-1), followed by the stroma (2.1 mU.mg protein-1) and epithelium (1.4 mU.mg protein-1). Similar results were obtained when SOD activity was expressed per DNA (5.03, 1.73, and 0.16 mU.micrograms DNA-1, respectively). Comparing the slope of the age-dependent regression lines, it was demonstrated that the slope of the stroma is much closer to the slope of the postmitotic skeletal muscle than the slope of the epithelium. From the data, it was calculated that the average life span of stromal cells is probably longer than 30 years and of epithelial cells longer than 2 years. Hence in human prostatic tissue the average cell death rate might be rather low.

Proceedings of the National Academy of Sciences, 2010

Neuroendocrinology, 2004

Ghrelin and the synthetic growth hormone secretagogues (GHSs) activate a G-protein-coupled recept... more Ghrelin and the synthetic growth hormone secretagogues (GHSs) activate a G-protein-coupled receptor (GHS-R) originally cloned from the pituitary, but which is also expressed in the hypothalamus, in other areas of the brain and in numerous peripheral tissues. Several studies have shown that growth hormone (GH)-releasing hormone (GHRH) is necessary for GHSs to exert maximal GH release in vivo. The exact mechanism of this synergism is not clear. Previous data suggest that GHSs can affect pituitary GHS-R mRNA expression; however, it is unknown whether this effect is age dependent and whether hypothalamic GHS-Rs are also affected. In this study, we tested whether (a) the synthetic GHS hexarelin regulates mRNA expression of its own receptor at the pituitary and/or hypothalamus and whether this effect is age dependent, and (b) whether short-term treatment with GHRH or, conversely, passive immunization against GHRH affects pituitary GHS-R1a mRNA expression in infant (10 days old) and young adult rats. GHS-R1a mRNA expression was measured with competitive reverse transcriptase-polymerase chain reaction. Hexarelin treatment significantly increased pituitary and hypothalamic GHS-R1a mRNA levels in normal infant rats, but not in normal young adult rats. In addition, hexarelin administration also stimulated pituitary GHS-R1a mRNA in infant as well as in young adult rats passively immunized against GHRH. GHRH treatment significantly enhanced pituitary GHS-R1a mRNA expression in GHRH-deprived young adult rats, though it did not affect the basal levels of GHS-R1a mRNA in normal infant and adult rats. These data further support the hypothesis that GHRH can affect GHS-R1a expression and that hexarelin upregulates the expression of its own receptor at the pituitary as well as the hypothalamus in an age-dependent fashion.

Molecular and Cellular Endocrinology, 2011

Ghrelin, the natural ligand for the growth hormone (GH)-secretagogue receptor (GHS-R), is produce... more Ghrelin, the natural ligand for the growth hormone (GH)-secretagogue receptor (GHS-R), is produced predominantly in the stomach. It is present in the circulation in two major forms, an acylated and an unacylated form, both of which have reported activities. Some of the best understood main effects of acylated ghrelin administration include anorexic effects, increased appetite and the stimulation of GH secretion. Ghrelin also seems to plays a role in glucose homeostasis, lipid metabolism and immune function. Based on its orexigenic and metabolic effects, ghrelin and ghrelin mimetics have potential benefit in antagonizing protein breakdown and weight loss in catabolic conditions such as cancer cachexia, renal, cardiac and pulmonary disease, and age-related frailty. Ghrelin also has potentially useful positive effects on cardiac function and gastric motility. Ghrelin antagonists may be of benefit to increase insulin sensitivity and potentiate weight loss. The following chapter presents some background on ghrelin and ghrelin assays and discusses some of the potential therapeutic approaches for the use of ghrelin, ghrelin mimetic compounds and ghrelin antagonists in clinical disease.

Molecular and Cellular Endocrinology, 2011

In humans, growth hormone (GH) is secreted from the anterior pituitary in a pulsatile pattern. Th... more In humans, growth hormone (GH) is secreted from the anterior pituitary in a pulsatile pattern. The traditional view is that this secretory pattern is driven by two counter regulatory neurohormones, GHRH and somatostatin. Ghrelin, the natural ligand for the growth hormone (GH)-secretagogue receptor (GHS-R), is produced in the stomach. Ghrelin is the strongest GH secretagogue known to date, but the role of endogenous ghrelin in the regulation of circulating GH levels remains controversial. The following review examines the evidence suggesting that endogenous ghrelin may be a key regulator of GH peak amplitude and discusses studies of diseases with altered GH levels, where it is found that in these states GH and ghrelin levels change in a similar way.