Biomedical subjects
R Payne
Publications and source records attributed to R Payne.
Measurement of cytosolic Ca2+ concentration in Limulus ventral photoreceptors using fluorescent dyes.
Several Ca-sensitive fluorescent dyes (fura-2, mag-fura-2 and Calcium Green-5N) were used to measure intracellular calcium ion concentration, Cai, accompanying light-induced excitation of Limulus ventral nerve photoreceptors. A ratiometric procedure was developed for quantification of Calcium Green-5N fluorescence. A mixture of Calcium Green-5N and a Ca-insensitive dye, ANTS, was injected in the cell and the fluorescence intensities of both dyes were used to calculate the spatial average of Cai within the light-sensitive R lobe of the photoreceptor. In dark-adapted photoreceptors, the initial Cai was 0.40 +/- 0.22 microM (SD, n = 7) as measured with fura-2. Cai peaked in the light-sensitive R lobe at 700-900 ms after the onset of an intense measuring light step, when the spatial average of Cai within the R lobe reached 68 +/- 14 and 62 +/- 37 microM (SD, n = 5) as measured with mag-fura-2 and Calcium Green-5N, respectively. The rate of Cai rise was calculated to be approximately 350 microM/s under the measuring conditions. The resting level of Mg2+ was estimated to be 1.9 +/- 0.9 mM, calculated from mag-fura-2 measurements. To investigate the effect of adapting light on the initial Cai level in the R lobe, a 1-min step of 420 nm background light was applied before each measurement. The first significant (P < 0.05) change in the initial level of Cai occurred even at the lowest adapting light intensity, which delivered approximately 3 x 10(3) effective photons/s. The relative sensitivity of the light-adapted photoreceptors was linearly related to the relative Cai on a double log plot with slope between -4.3 and -5.3. We were unable to detect a Cai rise preceding the light-activated receptor potential. The Cai rise, measured with Calcium Green-5N, lagged 14 +/- 5 ms (SD, n = 32) behind the onset of the receptor potential at room temperature in normal ASW. In the absence of extracellular Ca2+ and at 10 degrees C, this lag increased to 44 +/- 12 ms (SD, n = 17).
Guidelines for the clinical use of transdermal fentanyl.
Transdermal (TTS) fentanyl therapy has emerged as an effective alternative to the use of oral opioids for the control of pain in certain cancer patients. These patients are those with moderate to severe chronic pain, with a stable baseline pain pattern. Patients receiving this treatment should first be titrated to stable pain relief with oral opioids and should have recourse during therapy to fast-acting, short-duration analgesics for the control of incident pain. TTS fentanyl dosing schedules should be based upon the patient's requirement for rescue dosing and duration of effective pain control. The average requirement to change fentanyl patches is every 72 h, although 48-h dosing is necessary in a few patients. This novel route of fentanyl administration allows convenient outpatient treatment, the possibility of a lower incidence of side effects, and may thus aid compliance.
Intractable pain and suffering in a cancer patient.
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Subarachnoid neurolytic block under general anesthesia in a 3-year-old with neuroblastoma.
CASE REPORT: A 3-year-old boy with neuroblastoma complained of severe pain in the left lower extremity. Pharmacologic management had previously been attempted, but severe pain continued, and further upward titration was complicated by sedative effects. METHODS AND RESULTS: Because the focus of treatment had become the controlling of pain, a lumbosacral subarachnoid neurolytic block was performed under general anesthesia. One-time neurolysis was more acceptable to the family than a procedure like epidural analgesia, that requires greater management. Contrast medium was used to monitor the spread of the neurolytic. An epidural catheter was inserted during the neurolytic block procedure for possible future use. The short-term results were good--pain reports and opioid doses decreased greatly, although with increased incontinence. The boy had new abdominal distention and pain 5 days after neurolysis. Opioid doses and sedatives were increased. He died 3 days later.
New clinical-practice guidelines for the management of pain in patients with cancer.
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Preface: policy issues related to clinical practice guidelines.
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Facilitation of the responses to injections of inositol 1,4,5-trisphosphate analogs in Limulus ventral photoreceptors.
Injection of inositol 1,4,5-trisphosphate and its metabolically resistant analogs InsP3S3 and L-chiro-2,3,5-InsP3 into the ventral photoreceptors of Limulus results in the release of calcium from internal stores and in a current flow into the cells. We show here that the dependence of the current response on the amount of analog injected is supralinear. The injections also facilitate the responses to subsequent injections. We analyze the kinetics of the responses either by very slow application of the analogs directly into the lobe that is sensitive to InsP3 and light or by delivering a pulse into the nonsensitive lobe of the cell, in both cases creating a ramp of rising concentration in the sensitive region. Typically, a long latent period was followed by a strong brief inward current. The ratio between the latency and the duration of the response, defined as twice the time from half-amplitude to the peak of the response, reaches values greater than 10. Our analysis shows that this value cannot be attained within realistic models whose only nonlinearity is the cooperative binding of the ligand to its receptor. The observed ratio, however, can be achieved with a positive feedback model. Treatments that lead to partial depletion of calcium stores reversibly increase the latency of the response. We conclude that the mechanisms of the response of Limulus ventral eye to the metabolically resistant analogs of InsP3 probably involves a positive feedback mechanism and that the carrier of the feedback is likely to be Ca2+.
The latency of the response of Limulus photoreceptors to inositol trisphosphate lacks the calcium-sensitivity of that to light.
The latent period before depolarization of Limulus ventral photoreceptors by light flashes was compared with that following brief, intracellular, pressure-injection of d-myo-inositol 1,4,5 trisphosphate. At temperatures between 18 degrees C and 22 degrees C and with an extracellular calcium concentration of 10 mM, the responses of 4 cells to light and to injections of 100 microM inositol trisphosphate displayed average latencies of 71 and 56 ms, respectively. The latencies of responses to InsP3 included an estimated 20 ms dead-time inherent in the injection method. Reducing the temperature lengthened the latency of the response to light (Q10 approximately 3.2 between 7 and 22 degrees C) more than that to inositol trisphosphate (Q10 approximately 2.3). Bathing the photoreceptors in seawater containing no added calcium and 1 mM of the calcium chelator EGTA greatly increased the latency of the light response at all temperatures, but did not increase the latency of the response to inositol trisphosphate. We conclude that the response to inositol trisphosphate lacks the calcium- and temperature-sensitive latent period which characterizes the response to light. If inositol trisphosphate acts, via the release of stored calcium, to stimulate an intermediate in the visual cascade, then that intermediate would appear to be downstream from the latency-generating mechanism.
Effects of capsaicin on cutaneous vasodilator responses in humans.
The neurovascular responses to noxious electrically evoked axon reflex (EAR) stimulation and iontophoretic application of endothelium-dependent [acetylcholine (ACh)] and independent [sodium nitrite (NaNO2)] vasodilator substances were examined in human forearm skin using laser Doppler flowmetry, before and after repeated topical applications of the neurotoxin capsaicin (chronic capsaicin pre-treatment). Following 3 or 4 days of capsaicin pre-treatment the normal vasodilator response to acute application of capsaicin was significantly reduced as was the EAR response. There were, however, no significant changes in the vasodilator responses to either ACh or NaNO2, suggesting that the neurogenic axon reflex is in series with the endothelial and microvascular smooth muscle mechanisms of vasodilatation. Recovery of normal EAR occurred within 2-4 weeks of cessation of capsaicin pre-treatment.
Contouring structures for 3-dimensional treatment planning.
Three-dimensional (3-D) treatment planning is a labor-intensive process with contouring of the target volume and critical normal tissues being a significant time-consuming component. The use of 3-D treatment planning on a routine basis may be limited by the time required to complete treatment plans. Despite the need to increase the efficiency of the process, there is little literature addressing the speed and accuracy of contouring systems. In an attempt to initiate systematic analysis of the contouring process, data sets consisting of 10 CT images each were developed on two patients with esophageal carcinoma. Nine different operators manually contoured structures (target volume, spinal canal, lungs) on the data sets using four different contouring systems present in our department. These included both commercially available systems and those developed by the authors. There was a wide variation in the hardware and software characteristics of these systems. The time required to contour the CT data sets was recorded and analyzed. The contouring accuracy was assessed by comparison with a standard template derived from the CT data set for each image. The contouring time was found to be dependent on the system design, previous contouring experience, and the type of drawing instrument (lightpen vs mouse). The mean contouring time ranged from 26 minutes per patient for the fastest system to 41 minutes for the slowest. Potential clinically significant errors in contouring were rare for the spinal canal and lungs but present at a greater rate for the target volume (30.3%). The implications of this finding are discussed.
Transdermal fentanyl: suggested recommendations for clinical use.
Transdermal fentanyl offers the advantage of providing continuous administration of a potent opioid in the absence of needles and expensive drug-infusion pumps for the treatment of cancer pain. When transdermal fentanyl is initiated, it may be necessary to change the dose every 24-48 hr until an appropriate dose is titrated to the needs of the patient. This should be done by providing short-acting opioids as rescue analgesics for breakthrough pain. Well-accepted principles established for chronic opioid use in cancer pain management should apply to the administration of transdermal fentanyl as well. These include dose titration, the coadministration of adjuvant drugs to counteract opioid side effects and enhance analgesia, and the need to reassess the patient continuously for recurrent tumor and other new sources of pain. Further clinically relevant studies are needed and include 1) the determination of the relative potency of transdermal fentanyl, especially in comparison with oral and parenteral morphine; 2) a prospective study of the side-effect profile of transdermal fentanyl in relationship to oral morphine; and 3) the role of oral transmucosal administration of fentanyl in selection of starting doses of transdermal fentanyl and as a means to provide rescue doses for breakthrough pain.
Analgesia using vertebral venous plexus (Batson's Plexus) shunting of rectally administered opioids and anesthetics to the central nervous system.
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The management of intractable bone pain: a clinician's perspective.
Bone metastases occur in up to 85% of patients (at autopsy) who have breast, lung, and prostate cancer, and are a common cause of pain and neurological morbidity in patients with these and other cancers. The management of pain, the most common complication of bone metastasis, requires a knowledge of specific clinical syndromes and the associated neurological and orthopedic morbidities, as well as an understanding of current antitumor and pharmacological therapies. Knowledge of these potential complications are important in the design of clinical trials that seek to evaluate the effectiveness of new treatments for bone metastasis. Although radiation therapy in combination with analgesic drug therapies remains the mainstay of treatment, much recent interest in drugs with specific effects on bone elements, especially the osteoclast, offer the promise of providing effective pain relief with fewer side effects than is currently possible with conventional therapies.
Motor functions in rat hindlimb muscles following neonatal sciatic nerve crush.
The sciatic nerve was crushed in the right hindlimb in newborn (3-8 h old) rats. Two to four months later, electromyographic activity was recorded from both the control and reinnervated ankle extensor muscles soleus or lateral gastrocnemius and from the ankle flexor muscle tibialis anterior. Tonic postural activity was present in the extensor muscles on both sides during quiet stance. The control flexor muscles were usually silent in this situation, but the reinnervated flexors exhibited abnormal sustained activity. During locomotion, the control extensors were activated during the stance phase and their mean burst made up 61.5% of the step cycle. The control tibialis anterior muscle fired only during the swing phase, with the burst lasting 18.1% of the step cycle. In the reinnervated extensor muscles, the mean burst duration was decreased (46% of the cycle) but the basic locomotor pattern was not impaired. The reinnervated tibialis muscle, however, was activated abnormally, with one appropriate flexor burst during the swing phase and an "extensor-like" burst during the stance phase of the step. Reflex responses to stretch were weak or absent on the operated side. Histological examination showed that the reinnervated soleus and tibialis muscles were almost devoid of muscle spindles. The motor unit mean firing rates in the reinnervated soleus (22 imp/s) and lateral gastrocnemius (45 imp/s) matched those of the control muscles (25 and 42 imp/s, respectively). In contrast to the phasic, high-frequency firing (52-80 imp/s) in the control tibialis, the reinnervated tibialis motor units fired at significantly lower rates (22-56 imp/s).(ABSTRACT TRUNCATED AT 250 WORDS)
Injection of inositol trisphosphorothioate into Limulus ventral photoreceptors causes oscillations of free cytosolic calcium.
Limulus ventral photoreceptors contain calcium stores sensitive to release by D-myo-inositol 1,4,5 trisphosphate (InsP3) and a calcium-activated conductance that depolarizes the cell. Mechanisms that terminate the response to InsP3 were investigated using nonmetabolizable DL-myo-inositol 1,4,5 trisphosphorothioate (InsPS3). An injection of 1 mM InsPS3 into a photoreceptor's light-sensitive lobe caused an initial elevation of cytosolic free calcium ion concentration (Cai) and a depolarization lasting only 1-2 s. A period of densensitization followed, during which injections of InsPS3 were ineffective. As sensitivity recovered, oscillations of membrane potential began, continuing for many minutes with a frequency of 0.07-0.3 Hz. The activity of InsPS3 probably results from the D-stereoisomer, since L-InsP3 was much less effective than InsP3. Injections of 1 mM InsP3 caused an initial depolarization and a period of densensitization similar to that caused by 1 mM InsPS3, but no sustained oscillations of membrane potential. The initial response to InsPS3 or InsP3 may therefore be terminated by densensitization, rather than by metabolism. Metabolism of InsP3 may prevent oscillations of membrane potential after sensitivity has recovered. The InsPS3-induced oscillations of membrane potential accompanied oscillations of Cai and were abolished by injection of ethyleneglycol-bis (beta-aminoethyl ether)-N,N'-tetraacetic acid. Removal of extracellular calcium reduced the frequency of oscillation but not its amplitude. Under voltage clamp, oscillations of inward current were observed. These results indicate that periodic bursts of calcium release underly the oscillations of membrane potential. After each burst, the sensitivity of the cell to injected InsP3 was greatly reduced, recovering during the interburst interval. The oscillations may, therefore, result in part from a periodic variation in sensitivity to a constant concentration of InsPS3. Prior injection of calcium inhibited depolarization by InsPS3, suggesting that feedback inhibition of InsPS3-induced calcium release by elevated Cai may mediate desensitization between bursts and after injections of InsPS3.
Profound prolonged hypotension following captopril overdose.
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Pain syndromes in the cancer patient.
Paraneoplastic syndromes affect the nervous system in a very small percentage of patients with cancer. In those patients, portions of the nervous system are damaged or destroyed, usually in association with a small and often occult neoplasm elsewhere in the body. Current evidence suggests that these syndromes occur when the body mounts an immune response to an antigen shared between the tumor and the nervous system. The immune attack is then misdirected against that portion of the nervous system that possesses the "onconeural" antigen.