Biomedical subjects

Daniel L Marks

Publications and source records attributed to Daniel L Marks.

At least 19 recordsLinked to original sources

PubMed2006

Cachexia: lessons from melanocortin antagonism.

It is well established that disruptions in melanocortin signaling in the CNS result in morbid obesity, but only recently has evidence linked the activation of this system with the production of cachexia, also known as disease-associated wasting. Pro-opiomelanocortin-producing neurons, which express cytokine receptors, show increased activation in the presence of several cytokines that are increased in diseases that are associated with cachexia. Recent experiments show that blockade of melanocortin signaling using antagonists to the melanocortin MC(4) receptor attenuates disease-associated anorexia and wasting in rodent models of cancer and renal failure. This successful inhibition of cachexia is important because loss of appetite and lean body mass worsen the prognosis of many the diseases with which cachexia is associated.

Agouti-Related Protein↗

PubMed2006

High-spectral-resolution coherent anti-Stokes Raman scattering with interferometrically detected broadband chirped pulses.

To achieve high-spectral-resolution multiplex coherent anti-Stokes Raman scattering (CARS), one typically uses a narrowband pump pulse and a broadband Stokes pulse. This is to ensure a correspondence between anti-Stokes and vibrational frequencies. We obtain high-resolution CARS spectra of isopropanol, using a broadband chirped pump pulse and a broadband Stokes pulse, by detecting the anti-Stokes pulse with spectral interferometry. With the temporally resolved anti-Stokes signal, we can remove the chirp of the anti-Stokes pulse and restore high spectral resolution while also rejecting nonresonant scattering.

Equipment Design↗

PubMed2006

Therapy insight: Use of melanocortin antagonists in the treatment of cachexia in chronic disease.

Cachexia is a process that accompanies many chronic diseases, and consists of a combination of wasting of lean body mass, increased energy expenditure, and a paradoxical loss of appetite. Cachexia both worsens quality of life and negatively affects treatment of the underlying disease. Conditions as diverse as cancer, renal failure, and heart failure show a remarkable similarity in their associated cachexia, exhibiting changes in metabolism and endocrinology, including marked increases in levels of cytokines that accompany these diseases. So far, it has been difficult to treat disease-associated cachexia successfully. One treatment that has shown promise in animal trials, however, involves antagonism of the central melanocortin system, an anorexigenic pathway in the hypothalamus and brainstem. Humans who have genetic mutations involving pro-opiomelanocortin or the melanocortin 4 receptor in this pathway exhibit increased appetite and increased lean body mass. Recent research has shown that in rodent models of cancer and renal failure, administration of melanocortin 4 receptor antagonists results in an attenuation of symptoms of cachexia, including maintenance of appetite, lean body mass, and basal energy expenditure. Although this research needs to be substantiated in humans, it provides a promising direction for treating the wasting that is associated with a variety of disease states.

Animals↗

PubMed2006

Mechanisms of disease: Cytokine and adipokine signaling in uremic cachexia.

Clinical wasting is an important risk factor for mortality in uremic patients and is reported to have a prevalence of 30-60%. 'Malnutrition' is often inappropriately used to describe a group of nutritional abnormalities in uremic patients, which are characterized by anorexia, increased basal metabolic rate, loss of lean body mass, and declining levels of serum proteins. This syndrome--more accurately described as 'cachexia'--manifests as growth failure in children with uremia. Acidosis and inflammation are important causes of uremic cachexia but the underlying molecular mechanism is not well understood. Concentrations of circulating cytokines, such as leptin, tumor necrosis factor-alpha, interleukin-1, and interleukin-6, are elevated in patients with end-stage renal disease and correlate with the degree of cachexia in these individuals. Other energy-modulating hormones such as ghrelin, and adipokines such as adiponectin and resistin, are also perturbed in uremia and could contribute to nutritional abnormalities. We recently showed that elevated levels of circulating cytokines might be an important contributor to uremia-associated cachexia via signaling through the central melanocortin system. Small-molecule melanocortin antagonists, which are biologically active when administered orally or intraperitoneally, are now available and have been used successfully to ameliorate experimental cachexia. These findings could form the basis of a novel therapeutic strategy for uremic cachexia.

Adipose Tissue↗

PubMed2006

Anticatabolic properties of melanocortin-4 receptor antagonists.

PURPOSE OF REVIEW: Health problems related to weight regulation are increasingly common in the USA and around the world. Although obesity and associated complications garner the most attention in the media, clinical problems at the opposite end of the spectrum, such as involuntary disease-associated weight loss or cachexia, are equally devastating. This review focuses on the role of the central melanocortin system in body weight regulation, and specifically on the anticatabolic properties of antagonists of the melanocortin-4 receptor. RECENT FINDINGS: Over the past several years, the central melanocortin system has emerged as a major contributor to the body weight regulatory system in both animals and humans. In particular, the melanocortin-4 receptor, its endogenous agonist alpha-melanocyte stimulating hormone, and its endogenous antagonist agouti-related protein have been shown to be vital to the maintenance of normal body weight in both genetic and physiologic experiments. This system is now the target of multiple drug discovery endeavors, as the search continues for effective treatments for both obesity and cachexia. Several investigators have recently shown that selective synthetic antagonists of the melanocortin-4 receptor can prevent or attenuate the development of cachexia in animal models of acute and chronic disease. SUMMARY: An understanding of the biology of weight regulation, including both appetite regulation and energy metabolism, is vital if we are to unravel the etiology of and develop effective treatment for obesity and cachexia. The data reviewed here supporting a role for melanocortin-4 receptor antagonists in the treatment of catabolism represent an important advance in this field.

Animals↗

PubMed2006

Inverse scattering for optical coherence tomography.

Inverse scattering theory for optical coherence tomography (OCT) is developed. The results are used to produce algorithms to resolve three-dimensional object structure, taking into account the finite beam width, diffraction, and defocusing effects. The resolution normally achieved only in the focal plane of the OCT system is shown to be available for all illuminated depths in the object without moving the focal plane. Spatially invariant resolution is verified with numerical simulations and indicates an improvement of the high-resolution cross-sectional imaging capabilities of OCT.

Algorithms↗

PubMed2006

Inverse scattering for rotationally scanned optical coherence tomography.

Optical coherence tomography of luminal structures, such as for intravascular or gastrointestinal imaging, is performed by using a fiber-optic catheter as a beam-delivery probe. The interrogating beam is scanned angularly by rotating the fiber around a fixed central axis. Because the beam is focused only at a fixed distance from the center of the fiber, only scatterers near this distance are resolved. We present a solution of the inverse scattering problem that provides an estimate of the susceptibility of the sample for an angularly scanned Gaussian beam focused at a fixed distance from the origin. This solution provides quantitatively meaningful reconstructions while also extending the volume of the sample that is resolvable by the instrument.

Algorithms↗

PubMed2005

The regulation of food intake by selective stimulation of the type 3 melanocortin receptor (MC3R).

High levels of binding sites for melanocortin peptides exist within the arcuate nucleus, and a functional response to melanocortin peptides has been demonstrated in arcuate POMC neurons. Because the MC3R is thought to function as an inhibitory autoreceptor on POMC neurons, we reasoned that peripheral injections of MC3R-specific agonists would act within the arcuate nucleus to inhibit POMC neurons and thereby stimulate feeding. We demonstrate that the peptidergic MC3R agonist, d-Trp(8)-gamma-MSH, stimulates feeding via the MC3R when injected peripherally. These data provide the first evidence that feeding can be stimulated by peripheral injection of MC3R-specific agonists.

Animals↗

PubMed2005

The regulation of feeding and metabolic rate and the prevention of murine cancer cachexia with a small-molecule melanocortin-4 receptor antagonist.

Cachexia is metabolic disorder characterized by anorexia, an increased metabolic rate, and loss of lean body mass. It is a relatively common disorder, and is a pathological feature of diseases such as cancer, HIV infection, and renal failure. Recent studies have demonstrated that cachexia brought about by a variety of illnesses can be attenuated or reversed by blocking activation of the melanocortin 4 subtype receptor (MC4-R) within the central nervous system. Although the potential use of central MC4-R antagonists for the treatment of cachexia was supported by these studies, utility was limited by the need to deliver these agents intracerebroventricularly. In the current study, we present a series of experiments demonstrating that peripheral administration of a small molecule MC4-R antagonist can effectively stimulate daytime (satiated) food intake as well as decrease basal metabolic rate in normal animals. Furthermore, this compound attenuated cachexia and preserved lean body mass in a murine cancer model. These data clearly demonstrate the potential of small molecule MC4-R antagonists in the treatment of cachexia and underscore the importance of melanocortin signaling in the development of this metabolic disorder.

Animals↗

PubMed2005

Molecularly sensitive optical coherence tomography.

Molecular contrast in optical coherence tomography (OCT) is demonstrated by use of coherent anti-Stokes Raman scattering (CARS) for molecular sensitivity. Femtosecond laser pulses are focused into a sample by use of a low-numerical-aperture lens to generate CARS photons, and the backreflected CARS signal is interferometrically measured. With the chemical selectivity provided by CARS and the advanced imaging capabilities of OCT, this technique may be useful for molecular contrast imaging in biological tissues. CARS can be generated and interferometrically measured over at least 600 microm of the depth of field of a low-numerical-aperture objective.

Animals↗

PubMed2005

Orexigenic and anorexigenic mechanisms in the control of nutrition in chronic kidney disease.

Malnutrition is defined as abnormalities caused by an inadequate diet, but this term is often used inappropriately to describe the syndrome of loss of body weight with muscle mass being replaced by fatty tissue and declining serum proteins present in adults and children with chronic kidney disease (CKD). This syndrome is more accurately described as cachexia, and manifests as growth failure in children with CKD. Cachexia is common and is an important risk factor for poor quality of life and increased mortality and morbidity in both adults and children with CKD. Anorexia, acidosis and inflammation are important causes of cachexia, but the underlying molecular mechanism is not well understood. Dietary intake is often poor and resting metabolic rate is increased in CKD. The energy cost of growth is increased in experimental CKD. Circulating concentrations of cytokines, such as leptin, tumor necrosis factor-alpha and interleukins 1 and 6 are increased in patients with CKD and correlate with the degree of cachexia in these individuals. We hypothesize that cytokines signal through orexigenic neuropetides such as agouti-related peptide and neuropeptide Y (NPY), and anorexigenic neuropetides such as proopiomelanocortin and alpha-melanocyte-stimulating hormone in the arcuate nucleus in the hypothalamus. This signaling system also involves the NPY receptor and the melanocortin receptors and controls appetite and metabolic rate in health and disease. Furthermore, the first order neurons of this system are located outside the blood-brain barrier and can therefore sense the circulating levels of cytokines, as well as long-term satiety hormones such as leptin and insulin and short-term satiety hormones such as ghrelin and peptide (P) YY. There is experimental evidence that this hypothalamic neuropeptide signaling system may have an important role in the pathogenesis of cachexia in CKD. Understanding the molecular mechanism of cachexia in CKD may lead to novel therapeutic strategies.

Cachexia↗

PubMed2005

Deconvolution methods for mitigation of transverse blurring in optical coherence tomography.

Imaging resolution in optical coherence tomography (OCT) is a key determinant for acquiring clinically useful optical biopsies of tissues. In contrast to light or confocal microscopy, the axial and transverse resolutions in OCT are independent and each can be analyzed individually. A method for mitigating transverse blurring and the apparent loss of transverse resolution in OCT by means of Gaussian beam deconvolution is presented. Such a method provides better representation of a specimen by using known physical parameters of a lens. To implement this method, deconvolution algorithms based on a focal-dependent kernel are investigated. First, the direct inverse problem is investigated using two types of regularization, truncated singular value decomposition, and Tikhonov. Second, an iterative expectation maximization algorithm, the Richardson-Lucy algorithm, with a beam-width-dependent iteration scheme is developed. A dynamically iterative Richardson-Lucy algorithm can reduce transverse blurring by providing an improvement in the transverse point-spread-function for sparse scattering samples in regions up to two times larger than the confocal region of the lens. These deblurring improvements inside and outside of the confocal region, which are validated experimentally, are possible without introducing new optical imaging hardware or acquiring multiple images of the same specimen. Implementation of this method in sparse scattering specimens, such as engineered tissues, has the potential to improve cellular detection and categorization.

Algorithms↗

PubMed2005

Role of leptin and melanocortin signaling in uremia-associated cachexia.

The pathogenesis of cachexia in patients with uremia is unknown. We tested the hypothesis that uremia-associated cachexia is caused by leptin signaling through the hypothalamic melanocortin receptor 4 (MC4-R). We performed either subtotal nephrectomy (N) or sham operations in WT, leptin receptor-deficient (db/db), and MC4-R knockout (MC4-RKO) mice. The animals were on 17% protein diets, and none of the uremic animals were acidotic. WT-N mice produced a classic syndrome of cachexia characterized by decreased food intake, increased metabolic rate, and loss of lean body mass. Corrected leptin levels were elevated. db/db mice and MC4-RKO mice resisted the cachexic effects of uremia on weight gain, body composition, and metabolic rate. Likewise, treatment of WT mice with intracranial agouti-related peptide reversed the cachexic effects of uremia on appetite, weight gain, body composition, and metabolic rate. Gene expression of ubiquitin C and proteasome subunits C2, C3, and C9 was not changed in the uremic animals, suggesting that other pathways are involved in this model of nonacidotic uremic cachexia. The results of this study suggest that elevated circulating levels of cytokines such as leptin may be an important cause of uremia-associated cachexia via signaling through the central melanocortin system.

Agouti-Related Protein↗

PubMed2005

Optical biopsy of lymph node morphology using optical coherence tomography.

Optical diagnostic imaging techniques are increasingly being used in the clinical environment, allowing for improved screening and diagnosis while minimizing the number of invasive procedures. Diffuse optical tomography, for example, is capable of whole-breast imaging and is being developed as an alternative to traditional X-ray mammography. While this may eventually be a very effective screening method, other optical techniques are better suited for imaging on the cellular and molecular scale. Optical Coherence Tomography (OCT), for instance, is capable of high-resolution cross-sectional imaging of tissue morphology. In a manner analogous to ultrasound imaging except using optics, pulses of near-infrared light are sent into the tissue while coherence-gated reflections are measured interferometrically to form a cross-sectional image of tissue. In this paper we apply OCT techniques for the high-resolution three-dimensional visualization of lymph node morphology. We present the first reported OCT images showing detailed morphological structure and corresponding histological features of lymph nodes from a carcinogen-induced rat mammary tumor model, as well as from a human lymph node containing late stage metastatic disease. The results illustrate the potential for OCT to visualize detailed lymph node structures on the scale of micrometastases and the potential for the detection of metastatic nodal disease intraoperatively.

Animals↗

PubMed2005

Speckle reduction by I-divergence regularization in optical coherence tomography.

For optical coherence tomography (OCT), ultrasound, synthetic-aperture radar, and other coherent ranging methods, speckle can cause spurious detail that detracts from the utility of the image. It is a problem inherent to imaging densely scattering objects with limited bandwidth. Using a method of regularization by minimizing Csiszar's I-divergence measure, we derive a method of speckle minimization that produces an image that both is consistent with the known data and extrapolates additional detail based on constraints on the magnitude of the image. This method is demonstrated on a test image and on an OCT image of a Xenopus laevis tadpole.

Algorithms↗

PubMed2005

The use of melanocortin antagonists in cachexia of chronic disease.

Cachexia is a wasting syndrome that frequently develops in the setting of chronic diseases including cancer, congestive heart failure, chronic obstructive pulmonary disease, AIDS, renal failure and liver failure. Loss of lean body mass is believed to be a significant factor contributing to morbidity and mortality in these chronic diseases; however, there are currently no treatments available that have proven to be effective in reversing the progressive loss of lean body mass in cachectic patients. Evidence from animal models suggests a compelling link between inflammation, the central melanocortin system and cachexia. This review summarises the current evidence supporting the role of the melanocortin 4 (MC4) receptor subtype in cachexia, and discusses the development and use of small-molecule MC4 antagonists, which have proved to be effective in preventing the loss of lean body mass in animal models of cachexia. MC4 antagonists represent an attractive therapeutic approach for cachexia that may attenuate the loss of lean body mass in cachectic patients.

Animals↗

PubMed2005

MC4 receptor antagonists: a potential treatment for cachexia.

Cachexia (involuntary weight loss) is a devastating syndrome associated with many chronic diseases including cancer, and heart, lung, kidney and liver failure. There are currently no effective treatments capable of reversing the loss of lean body mass that is believed to be a major contributor to morbidity and mortality in these chronic diseases. Recent findings strongly indicate that blockade of central melanocortin signaling through the MC4 receptor subtype attenuates cachexia. This review summarizes the evidence supporting the role of MC4 receptors in cachexia, and highlights the progress achieved in the development of small-molecule MC4 antagonists, which have recently proved to be effective in animal models of cachexia. MC4 antagonists are an attractive therapeutic approach for cachexia that may ameliorate the loss of lean body mass in cachectic patients.

Animals↗

PubMed2004

A role for agouti-related protein in appetite regulation in a species with continuous nutrient delivery.

Knowledge of specific neurotransmitters as well as the pathways and mechanisms regulating appetite in ruminants that continually graze, such as sheep, is incomplete. Although fundamentally agouti-related protein (AGRP) has a similar function across species to increase food intake, the regulation of AGRP may vary across grazing and intermittent feeders. To investigate the role of orexigenic peptides in the regulation of feed intake, we first extracted messenger RNA from sheep that were fasted for 3 days, which was then used for PCR followed by cloning and sequencing to demonstrate the presence of hypothalamic AGRP expression. Ovine AGRP was closely related to the bovine, but contained sequence differences with human and mouse AGRP. Analysis of genomic DNA also revealed a similar gene structure to other published species. Secondly, using dual-labeled immunohistochemistry, we determined that there was both increased AGRP immunoreactivity and increased abundance of c-Fos immunoreactivity in AGRP neurons in the arcuate nucleus of fasted sheep. Because AGRP neurons are activated by fasting, we hypothesized that AGRP would stimulate feeding in this ruminant species. Sheep fed ad libitum were injected intracerebroventricularly with concentrations of AGRP at 0.2 and 2.0 nmol/kg. AGRP at 2.0 nmol/kg significantly increased food intake at 4, 6 and 12 h (p < 0.05). A 4th study was done to investigate the interactions of AGRP and neuropeptide Y (NPY) on food intake over a 24-hour period. Intracerebroventricular injections of either AGRP or NPY significantly increased cumulative food intake over saline controls. When AGRP and NPY were injected in combination, food intake was increased over saline controls; however, AGRP did not potentiate the effects of NPY. These results demonstrate that AGRP stimulates food intake in sheep and highlights the important differences between this species and rodent models.

Agouti Signaling Protein↗