Thomas L. Talbot

A controlled trial of naloxone infusions for the pruritus of chronic cholestasis.

To test the hypothesis that opioid agonist activity contributes to the pruritus of cholestasis, a placebo-controlled single-blinded trial of naloxone, an opioid antagonist, was conducted in eight patients with primary biliary cirrhosis. After discontinuation of all conventional antipruritic medications, one or two continuous (24-hour) IV infusions of naloxone (0.2 micrograms.kg-1.min-1) and placebo solution were administered consecutively in an order that was not predetermined. Pruritus was assessed subjectively by means of four hourly recordings of a visual analogue score. In addition, objective measurements of scratching activity that were independent of gross body movements were continuously recorded using an apparatus specifically designed to measure the frequencies associated with this activity. No side effects associated with naloxone infusions were observed. Only scratching activity data obtained for the same periods of day and night during both naloxone and placebo infusions were compared. Naloxone infusions were consistently associated with a decrease in values of the scratching activity index. In addition, in 50% of the patients the infusions were associated with a decrease in visual analogue score. The mean decrease in scratching activity ranged from 29% to 96% (mean, 50%; P less than 0.001). These findings imply that increased opioid agonist activity contributes to scratching activity in cholestatic patients.

Oral nalmefene therapy reduces scratching activity due to the pruritus of cholestasis: a controlled study.

BACKGROUND Intravenous naloxone frequently ameliorates the pruritus of cholestasis, but its low oral bioavailability precludes its use as a long-term therapy. Nalmefene is an orally bioavailable opiate antagonist. OBJECTIVE We assessed the efficacy of oral nalmefene in ameliorating the pruritus of cholestasis. METHODS In a prospective controlled study conducted in a tertiary referral hospital, 11 patients with generalized pruritus complicating chronic liver disease were randomized to receive either nalmefene or placebo in a double-blinded fashion for 2-month periods. Scratching activity was measured continuously for 24-hour periods at baseline and at the end of each treatment period. RESULTS Data on 8 patients who received at least 1 course of nalmefene were available for comparison with corresponding control data, which consisted of observations obtained during a course of placebo and/or at baseline. Nalmefene therapy was associated with a 75% reduction in the geometric mean hourly scratching activity (P <.01) and a decrease in the mean of a visual analogue score of the perception of pruritus in all 8 patients (mean decrease 77%, P <.01). CONCLUSION Oral administration of nalmefene can ameliorate pruritus complicating chronic liver disease.

The local effects of cachectin/tumor necrosis factor on wound healing

Previous experimental studies have suggested that tumor necrosis factor (TNF) may have either a beneficial or a detrimental role in wound healing. Control and doxorubicin-treated (6 mg/kg, intravenously) rats underwent paired dorsal 5-cm linear wounds and had either vehicle or recombinant (r)TNF (0.5, 5, or 50 fig) applied locally to the wound. Paired wounds were harvested at 7 and 14 days after wounding and analyzed for wound-bursting strength (WBS) and activity of the gene for type 1 collagen and TNF. Doxorubicin treatment decreased WBS at 14 days but not at 7 days after wounding/Local application of 50 fig of rTNF decreased WBS in saline-treated rats and concentrations of 5 and 50 μg decreased WBS in doxorubicin-treated rats when measured 7 days after wounding. These effects dissipated when WBS was measured 14 days after wounding. Doxorubicin decreased wound collagen gene expression and local TNF treatment decreased wound collagen gene expression in saline-treated rats and further decreased it in doxorubicin-treated rats. The decrement in collagen gene expression induced by rTNF increased as the local dose of rTNF increased. The gene for TNF was not detectable in wounds from normal or doxorubin-treated rats at 3,7,10, or 14 days after wounding. These data suggest that the gene for TNF is not expressed in wounds and that the local application of TNF is detrimental to wound healing as it decreases WBS and activity of the gene for collagen.

A novel, variable angle guide grid for neuronal activity studies

Introduction: Surgically implanted chambers with removable grids are routinely used for studying patterns of neuronal activity in primate brains; however, accessing target tissues is significantly constrained by standard grid designs. Typically, grids are configured with a series of guide holes drilled vertically, parallel to the walls of the chamber, thus targeted sites are limited to those in line vertically with one of the guide holes. Methods: By using the three-dimensional modeling software, a novel grid was designed to reach the targeted sites far beyond the standard reach of the chamber. The grid was fabricated using conventional machining techniques and three-dimensional printing. Results: A pilot study involving microinjection of the magnetic resonance (MR) contrast agent gadolinium into the discrete regions of interest (ROIs) in the temporal cortex of an awake, behaving monkey demonstrated the effectiveness of this new design of the guide grid. Using multiple different angles of approach, we were readily able to access 10 injection sites, which were up to 5 mm outside the traditional, orthogonal reach of the chamber.

Cross-sectional tongue shape during the production of vowels

This study used ultrasound imaging to examine the cross-sectional shape of the tongue during the production of the ten English vowels ( see text ) in two consonant contexts--/p/ and /s/--and at two scan angles--anterior and posterior. Results were compared with models of sagittal tongue shape. A newly built transducer holder and head restraint maintained the ultrasound transducer in a fixed position inferior to the mandible at a chosen location and angle. The transducer was free to move only in a superior/inferior direction, and demonstrated reliable tracking of the jaw. Since the tongue is anisotrophic along its length, anterior and posterior scan angles were examined to identify differences in tongue shape. Similarly, the coarticulatory effects of the sibilant /s/ versus the bilabial /p/ were examined, to assess variability of intrinsic tongue shape for the vowels. Results showed that the subjects midsagittal tongue grooving was almost universal for the vowels. Posterior grooves were deeper than anterior grooves. In /s/ context, posterior tongue grooves were shallower than in /p/ context. Anteriorly, /s/ context caused deeper grooves for low vowels. Cross-sectional tongue shape varied with tongue position similarly to sagittal tongue shape.

The Effect of Ultrasonic and Thermal Treatment on Wounds

A method of local treatment of wounds to accelerate healing would be a major benefit in those patients in whom abnormal healing is expected. Earlier studies has suggested that local ultrasonic treatment of wounds would stimulate the healing process. We have evaluated the effect of local ultrasound (5 MHz) and thermal treatments on healing in a dermal wound model. Various intensities of ultrasound and heat were employed for 5 min/day (0.05 W/cm2) and 10 min/day (0.05W/cm2), with healing assessed by wound breaking strength measurements obtained 14 days after injury. Subcutaneous temperature measurements demonstrated that equal intensities of ultrasound and heat produced equivalent temperature changes in the tissues. None of the treatments employed resulted in greater wound breaking strengths than the controls, and the higher intensities of ultrasound (0.1 and 0.15 W/cm2) and heat (0.15 W/cm2) resulted in decreased wound breaking strength. Our results failed to support brief daily treatments of local ultrasound or heat as stimulants of wound healing.

The effect of testosterone propionate on wound healing in normal and castrate rats

Abstract The dependence of wound healing on testosterone was studied in normal and castrate rats by determination of wound breaking strength (WBS) in dermal wounds, by implantation of subcutaneous polyvinyl sponges (PVS) and by [ 3 H]proline tracer studies. The level of testosterone achieved with various doses of testosterone propionate (TP) was assessed using the androgenic effect of this hormone on prostate and seminal vesicle weights. Exogenous testosterone propionate (0.25 – 3.0 mg/day) produced no acceleration of wound healing as measured by WBS on 14- and 21-day wounds. In castrate rats a mild inhibition of healing (15% decrease in WBS) was found in 14-day wounds but no difference was found between castrate and control in 21-day wounds. The rate of wound collagen synthesis was assessed by measuring the conversion of [ 3 H]proline to [ 3 H]hydroxyproline, a process essentially limited to procollagen synthesis. It was not altered by castration, or by administration of testosterone propionate (0.0625 – 1.0 mg/day) to castrate rats. Similarly, deposition of tissue in polyvinyl sponges whether measured as added dry weight or total hydroxyproline did not differ significantly between control and castrate rats receiving testosterone propionate (0–1.0 mg/day). As a method of assessing wound healing, WBS measurements produced the most consistent results. In conclusion, no longterm dependence of wound healing on testosterone was identified in the testosterone-depleted (castrate) rat although some early depression was noted, and no acceleration of the normal process resulted from exogenous testosterone administration in the normal or testosterone-depleted rat.

High channel count single-unit recordings from nonhuman primate frontal cortex

BACKGROUND Single unit recording in behaving nonhuman primates is widely used to study the primate central nervous system. However, certain questions cannot be addressed without recording large numbers of neurons simultaneously. Multiple 96-electrode probes can be implanted at one time, but certain problems must be overcome to make this approach practical. NEW METHOD We describe a series of innovations and practical guidance for implanting and recording from 8 arrays of 96 electrodes (768 electrodes) in the frontal cortex of Macaca mulatta. The methods include an individualized 3D-printed connector mounting platform, sequencing of assembly and surgical steps to minimize surgery time, and interventions to protect electrical connections of the implant. RESULTS The methodology is robust and was successful in our hands on the first attempt. On average, we were able to isolate hundreds (535.7 and 806.9 in two animals) of high quality units in each session during one month of recording. COMPARISON WITH EXISTING METHODS To the best of our knowledge, this technique at least doubles the number of Blackrock arrays that have been successfully implanted in single animals. Although each technological component was pre-existing at the time we developed these methods, their amalgamation to solve the problem of high channel count recording is novel. CONCLUSIONS The implantation of large numbers of electrodes opens new research possibilities. Refinements could lead to even greater capacity.

Open-label trial of oral nalmefene therapy for the pruritus of Cholestasis

The aims of this study were to determine whether long-term oral administration of the opiate antagonist nalmefene is associated with any beneficial effects in patients with pruritus secondary to cholestatic liver disease and to assess the safety of long-term administration of this drug to these patients. Fourteen patients with unrelieved chronic pruritus of cholestasis were studied. Scratching activity, independent of limb movements, was recorded continuously for 24-hour periods before and during treatment with an initial ameliorating dose of nalmefene. Simultaneously, during these periods, visual analogue scores (VASs) of pruritus were recorded every 4 hours while patients were awake. The dose of nalmefene, which initially was 2 mg orally twice daily, was increased during the study, usually until a satisfactory clinical response was achieved. Five patients experienced a transient opioid withdrawal-like reaction that did not preclude continuing with nalmefene therapy. Serum biochemical indices of cholestasis did not change appreciably during treatment. Thirteen patients reported amelioration of the perception of pruritus on nalmefene. In 5 patients, exacerbations of pruritus occurred approximately 4 weeks after an initial ameliorating dose had been reached; these exacerbations were managed by increasing the dose. Baseline mean values for VAS and scratching activity were higher than corresponding means during nalmefene therapy in 13 (P = .002) and 12 (P = .013) patients, respectively. Possible tolerance to nalmefene occurred in 3 patients. Three patients experienced marked exacerbation of pruritus after nalmefene therapy was suddenly discontinued. Blood levels of nalmefene were consistent with normal pharmacokinetics of the drug. These results suggest that nalmefene may have a favorable risk-to-benefit ratio when it is administered orally long-term to patients with the pruritus of cholestasis.

Strain rate dependency of wound breaking strength for the dermal wound model

Male Fischer rats were given a full thickness, dorsal midline wound with a scalpel, and the wound was closed with 9-mm clips at 1-cm intervals. At postoperative day 14 the rats were sacrificed and wound-breaking strengths (WBS) for various strain rates were determined. The results demonstrated a dramatic dependence of WBS on strain rate.<<ETX>>