Publications

Melanocortins (MSH's) are three structurally related peptides derived from proopiomelanocortin. They regulate several physiologic functions including energy metabolism, appetite, and inflammation. Recent work in rodents has also identified important effects of MSH's, particularly γ-MSH, on sodium metabolism and blood pressure regulation. Normal rats and mice respond to a high sodium diet with an increase in the plasma concentration of γ-MSH, and remain normotensive, while those with genetic or pharmacologic γ-MSH deficiency become hypertensive on a high sodium diet. This hypertension is corrected by exogenous administration of the peptide. Mice lacking the γ-MSH receptor (the melanocortin 3 receptor, Mc3r) also become hypertensive on a high sodium diet but remain so when administered γ-MSH, and infusions of physiologic levels of the peptide stimulate urinary sodium excretion in normal rats and mice, but not in mice with deletion of Mc3r. The salt-sensitive hypertension in rodents with impaired γ-MSH signaling appears due to stimulation of noradrenergic activity, since plasma noradrenaline is increased and the hypertension is rapidly corrected with infusion of the α-adrenoceptor antagonist phentolamine. In contrast to the antihypertensive property of physiologic levels of γ-MSH, intravenous or intracerebroventricular injections of high levels of the peptide raise blood pressure. This occurs in mice lacking Mc3r, indicating an interaction with some other central receptor. Finally, the salt-sensitive hypertension in rodents with disruption of γ-MSH signaling is accompanied by insulin resistance, an observation which offers a new window into the study of the association of salt-sensitive hypertension with insulin resistance and type II diabetes.

Proteases are the most abundant class of proteins produced by mast cells. Many of these are stored in membrane-enclosed intracellular granules until liberated by degranulating stimuli, which include cross-linking of high affinity IgE receptor F(c)εRI by IgE bound to multivalent allergen. Understanding and separating the functions of the proteases is important because expression differs among mast cells in different tissue locations. Differences between laboratory animals and humans in protease expression also influence the degree of confidence with which results obtained in animal models of mast cell function can be extrapolated to humans. The inflammatory potential of mast cell proteases was the first aspect of their biology to be explored and has received the most attention, in part because some of them, notably tryptases and chymases, are biomarkers of local and systemic mast cell degranulation and anaphylaxis. Although some of the proteases indeed augment allergic inflammation and are potential targets for inhibition to treat asthma and related allergic disorders, they are protective and even anti-inflammatory in some settings. For example, mast cell tryptases may protect from serious bacterial lung infections and may limit the "rubor" component of inflammation caused by vasodilating neuropeptides in the skin. Chymases help to maintain intestinal barrier function and to expel parasitic worms and may support blood pressure during anaphylaxis by generating angiotensin II. In other life-or-death examples, carboxypeptidase A3 and other mast cell peptidases limit systemic toxicity of endogenous peptideslike endothelin and neurotensin during septic peritonitis and inactivate venom-associated peptides. On the other hand, mast cell peptidase-mediated destruction of protective cytokines, like IL-6, can enhance mortality from sepsis. Peptidases released from mast cells also influence nonmast cell proteases, such as by activating matrix metalloproteinase cascades, which are important in responses to infection and resolution of tissue injury. Overall, mast cell proteases have a variety of roles, inflammatory and anti-inflammatory, protective and deleterious, in keeping with the increasingly well-appreciated contributions of mast cells in allergy, tissue homeostasis and innate immunity.

OBJECTIVE

Systemic lupus erythematosus (SLE) primarily affects women of reproductive age. Here we summarize the scientific evidence supporting recently developed quality indicators (QIs) pertaining to reproductive health.

METHODS

We used a modification of the RAND/UCLA Appropriateness Method to develop QIs for SLE. We performed systematic reviews of the literature pertaining to each proposed indicator. Three indicators focusing on reproductive health were included in the final set. Relevant literature was presented to an expert panel, who rated the validity and feasibility of the indicators.

RESULTS

Three QIs were rated as valid and feasible. These indicators specifically address laboratory testing during pregnancy in SLE, the treatment of antiphospholipid antibody syndrome, and counseling for drugs with teratogenic potential.

CONCLUSION

We used a rigorous method to develop reproductive health QIs for SLE. In the future, these indicators can be used in the assessment and delivery of care to patients with SLE.

Chronic peripheral neuropathic pain is the result of abnormal activity in sensory nerves. It is well recognized that this sensory nerve dysfunction can be caused by traumatic, toxic, or metabolic insult to the nerve. In addition, there is growing recognition that neuropathic pain is a frequent manifestation of neurodegenerative diseases. In this regard, important clues to the cellular mechanisms of neuropathic pain may be found by close examination of neurodegenerative diseases (including Parkinson's disease) in which neuropathic pain is often an underappreciated but important clinical manifestation. This approach identifies specific mitochondrial and cytoskeletal mechanisms, previously implicated in the pathophysiology of neurodegenerative diseases in the central nervous system, that might contribute to neuropathic dysfunction in peripheral sensory nerve fibers. Investigations in preclinical models of common peripheral neuropathic pain conditions have supported the idea that a subset of these cellular mechanisms of neurodegeneration can produce painful hyperactivity in primary afferent nociceptors. Importantly, this emerging concept of neurodegenerative disease mechanisms in the primary afferent nociceptor identifies novel molecular targets for the treatment neuropathic pain.

Predictive and prognostic biomarkers offer a potential means to personalize cancer medicine, although many reach the market-place before they have been validated, and their adoption is often hindered by variable clinical evidence. Because of this variability in supporting evidence, clinical practice guidelines formulated by panels of subspecialty experts may be particularly important in guiding stakeholders' acceptance and use of new personalized medicine biomarker tests and other nascent technologies. This article provides a structured review of the clinical evidence supporting 4 contemporary biomarker tests in colorectal cancer: K-ras and B-raf mutation analyses, mismatch repair protein testing, and the Oncotype DX Colon Cancer Assay. All 4 tests have been evaluated for guideline inclusion by the NCCN Guidelines Panel for Colon Cancer. This case study shows significant variability in the level of clinical evidence associated with these tests. In the cases of B-raf and mismatch repair protein testing, the available evidence is also inconsistent as it pertains to the specific NCCN Guideline recommendation. Based on this uncertainty in the evidence base, the authors conclude that expert clinical judgment, experience, and consensus may be more heavily weighted than published clinical trial data in the evaluation of new personalized medicine biomarker tests. Potential implications of this conclusion and future directions for research are discussed.

We conducted a study designed to evaluate the efficacy and feasibility of a multilevel self-management intervention to improve nutritional intake in a group of older adults receiving Medicare home health services who were at especially high risk for experiencing undernutrition. The Behavioral Nutrition Intervention for Community Elders (B-NICE) trial used a prospective randomized controlled design to determine whether individually tailored counseling focused on social and behavioral aspects of eating resulted in increased caloric intake and improved nutrition-related health outcomes in a high-risk population of older adults. The study was guided by the theoretical approaches of the Ecological Model and Social Cognitive Theory. The development and implementation of the B-NICE protocol, including the theoretical framework, methodology, specific elements of the behavioral intervention, and assurances of the treatment fidelity, as well as the health policy implications of the trial results, are presented in this article.