Sensing muscle ischemia: coincident detection of acid and ATP via interplay of two ion channels.

Ischemic pain--examples include the chest pain of a heart attack and the leg pain of a 30 s sprint--occurs when muscle gets too little oxygen for its metabolic need. Lactic acid cannot act alone to trigger ischemic pain because the pH change is so small. Here, we show that another compound released from ischemic muscle, adenosine tri-phosphate (ATP), works together with acid by increasing the pH sensitivity of acid-sensing ion channel number 3 (ASIC3), the molecule used by sensory neurons to detect lactic acidosis. Our data argue that ATP acts by binding to P2X receptors that form a molecular complex with ASICs; the receptor on sensory neurons appears to be P2X5, an electrically quiet ion channel. Coincident detection of acid and ATP should confer sensory selectivity for ischemia over other conditions of acidosis.

Enzymes that synthesize the IB4 epitope are not sufficient to impart IB4 binding in dorsal root ganglia of rat.

The isolectin B4 (IB4) stains a subset of small and medium-sized dorsal root ganglion (DRG) neurons by binding to terminal alpha-galactose on glycoproteins and glycolipids. The enzymes alpha(1,3)galactosyltransferase (1,3GT) and isoglobotriaosylceramide synthase (iGb3S) synthesize the galactose-alpha(1,3)-galactose group, which is the most common carbohydrate containing terminal alpha-galactose. 1,3GT preferentially glycosylates proteins whereas iGb3S glycosylates lipids. We generated antibodies against rat 1,3GT and iGb3S that were used for immunohistochemical staining of DRG cells. Virtually all neurons that bound IB4 expressed both enzymes, suggesting that IB4 binds to both glycoproteins and glycolipids in IB4-positive neurons. 1,3GT immunoreactivity was observed in small and medium-sized neurons and satellite cells. iGb3S immunoreactivity was observed in neurons of varying sizes. Many neurons that expressed these enzymes did not bind IB4. Additionally, the majority of neurons that expressed substance P expressed both enzymes but did not bind IB4. Ultrastructual studies revealed that 1,3GT was predominantly associated with the Golgi apparatus, whereas iGb3S was found near the Golgi apparatus and in large, clear vesicles throughout the soma. These data suggest that, although expression of 1,3GT and/or iGb3S appears to be necessary for IB4 binding, expression of these enzymes is not sufficient to impart IB4 binding.

Outcome evaluation of a randomized trial of the PhoenixCare intervention: program of case management and coordinated care for the seriously chronically ill.

OBJECTIVE: To document outcomes of a randomized trial of the PhoenixCare demonstration program of palliative care and coordinated care/case management for seriously chronically ill individuals who simultaneously received active treatment from managed care organizations (MCOs). DESIGN: Patients, continuously enrolled between July 1999, and March 2001, were randomly assigned to the PhoenixCare program or a control group receiving usual MCO care. SETTING: Hospice of the Valley, Phoenix, Arizona. PARTICIPANTS: Participants were 192 patients with chronic obstructive pulmonary disease (COPD) or chronic heart failure (CHF), who had an estimated 2-year life expectancy. INTERVENTION: Intensive home-based case management provided by registered nurse casemanagers, in coordination with patients' existing source of medical care, comprised the intervention. Program foci included disease and symptom management, patient self-management of illness and knowledge of illness-related resources, preparation for end-of life, physical and mental functioning, and utilization of medical services. OUTCOME MEASURES: Outcomes, assessed every 3 months by telephone interview, included measures related to all program foci; the SF-36 was used to evaluate physical and mental functioning; emergency department visits exemplified medical service utilization. RESULTS: Compared to controls, PhoenixCare patients exhibited significantly better outcomes on self-management of illness, awareness of illness-related resources, and legal preparation for end of life. They reported lower symptom distress, greater vitality, better physical functioning and higher self-rated health than randomized controls. Emergency department utilization was equivalent across groups. Patients with COPD showed stronger responsiveness to the intervention. CONCLUSION: A novel model of patient care that combined greatly enhanced palliative carefocused case management with ongoing MCO-based treatment was associated with improved functioning of chronically severely ill patients in the last years of life.

Effects of peripheral nerve injury on delta opioid receptor (DOR) immunoreactivity in the rat spinal cord.

Morphine and other opioids have direct analgesic actions in the spinal cord and chronic spinal administration of opioid agonists is used clinically in patients suffering from severe, chronic pain. Neuropathic pain resulting from peripheral nerve injury is often less sensitive to opioid therapy than other forms of chronic pain in both humans and animal models. Changes in spinal mu-opioid receptor (MOR) expression have been demonstrated in animal models of neuropathic pain. However, these changes alone fail to account for the attenuation of opioid activity. Reduced expression of delta-opioid receptors (DOR) following peripheral nerve injury has been reported but most of these reports are limited to subjective observation. The magnitude and consistency of these changes is therefore unclear. In addition, previous studies did not evaluate the effects of nerve injury on behavioral measures to confirm induction of aberrant pain symptoms. We therefore performed quantitative image analysis to evaluate the effect of peripheral nerve injury on DOR-immunoreactivity in spinal cord sections from rats previously characterized for sensory responsiveness. We observed statistically significant decreases ipsilateral to nerve injury in all three models tested: sciatic nerve transection, chronic constriction injury of the sciatic nerve and L5/L6 spinal nerve ligation. These results suggest that decreases in the expression of DOR are a common feature of peripheral nerve injury.

The PhoenixCare Program.

In response to a perceived need for patient access to palliative care and supportive services prior to hospice eligibility, Phoenix-based Hospice of the Valley (HOV) applied for and received a 3-year demonstration grant (1999-2001) from The Robert Wood Johnson (RWJ) Promoting Excellence in End-Of-Life Care Project. HOV established the PhoenixCare project as a demonstration of palliative and coordinated care (case management) services for seriously chronically ill individuals still undergoing active treatment of their disease within a managed care setting. The model emphasized patient/family self-empowerment and prevention. The goal was to demonstrate that it was possible to expand the scope of care for the seriously chronically ill, add palliative care, and improve patient quality of life at less (or no more) cost than that for a comparable group of managed care patients not receiving PhoenixCare services. The model proved most useful to patients willing and able to assume a degree of control over their own care. Physicians referred fewer than 5% of the patients enrolled while managed care plan case managers and hospital discharge planners referred 83%, suggesting that in organized systems of care physicians are not a primary source for patient referrals. The structure and content of the PhoenixCare model, its general acceptability to patients, physicians and managed care plans, and its applicability to other sites are discussed in this article. Outcomes from the study will be published in a subsequent paper.